AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-...AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aido-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rvl cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family I member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family I member C3 enzyme activity and the inhibition of 22Rvl prostate cancer cell growth by decreasing the intfacellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKRlC3 inhibitors using berberine as the lead compound.展开更多
The US Preventive Services Task Force （USPSTF） analyzed the benefits and harms of prostate specific antigen （PSA）- based screening for prostate cancer （PCa）. The Grade ＇D＇ recommendation of the USPSTF was base...The US Preventive Services Task Force （USPSTF） analyzed the benefits and harms of prostate specific antigen （PSA）- based screening for prostate cancer （PCa）. The Grade ＇D＇ recommendation of the USPSTF was based mainly on the Prostate, Lung, Colorectal, and Ovarian （PLCO） study in the United States. That result showed only a small reduction in PCa mortality. However, the data from the International Agency for Research on Cancer （IARC） iUustrated the PCa mortality rate （MR） decreased marked. To avoid the over-diagnosis and over-treatment, the American Cancer Society has changed its strategy and updated its guidance. The USPSTF neglected the aggressive PCa accounted for more then 30% of all PCa. Highly aggressive PCa can be diagnosed by PSA screening combined with Gleason grade. We hope that the USPSTF changes the ＇D＇ recommendation for PSA screening.展开更多
The recent manuscript in New England Journal of Medicine by Antonarakis et al. has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 （AR-V7）, in...The recent manuscript in New England Journal of Medicine by Antonarakis et al. has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 （AR-V7）, in circulating tumor cells （CTCs） from metastatic castrate-resistant prostate cancer （mCRPC） patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen （PSA） responses.展开更多
The ability of epithelial neoplasms to evade both hormonal and cytotoxic therapies is self-evident as the common carcinomas （lung, stomach, breast, colon and prostate） at their metastatic stage are rarely curable wi...The ability of epithelial neoplasms to evade both hormonal and cytotoxic therapies is self-evident as the common carcinomas （lung, stomach, breast, colon and prostate） at their metastatic stage are rarely curable with current therapies. Though the precise reasons for incurability are debated,展开更多
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metasta...The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.展开更多
The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myelo...The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myeloid cell differentiation. A small number of simple and complex variants of the classical t(15;17) have been reported. We report two complex three-way translocation variants,t(3;17;15)(q27;q21;q22) and t(8;17;15)(q24.3;q12;q22) in which the PML/RARA fusion gene has been created on the derivative 15 chromosomes. Many of these variant translocations are suspected by conventional cytogenetics but need to be confirmed with additional molecular testing. We discuss the importance of supplementing conventional cytogenetic testing with FISH and RT-PCR to accurately diagnose APL variant patients.展开更多
Lipids are essential for mammalian cells to maintain many physiological functions. Emerging evidence has shown that cancer cells can develop specific alterations in lipid biosynthesis and metabolism to facilitate thei...Lipids are essential for mammalian cells to maintain many physiological functions. Emerging evidence has shown that cancer cells can develop specific alterations in lipid biosynthesis and metabolism to facilitate their survival and various malignant behaviors. To date, the precise role of cellular lipids and lipid metabolism in viral oncogenesis is still largely unclear with only a handful of literature covering this topic to implicate lipid metabolism in oncogenic virus associated pathogenesis. In this review, we focus on the role of lipid biosynthesis and metabolism in the pathogenesis of the Kaposi's sarcoma-associated herpesvirus, a common causative factor for cancers arising in the immunocompromised settings.展开更多
Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers...Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called ‘gain-of-functions’(GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.展开更多
Breast cancer （BC） is the most malignant cancer and the second leading cause of deaths in women worldwide. It is typically classified into the following three subtypes： estrogen receptor （ER）/progesterone recept...Breast cancer （BC） is the most malignant cancer and the second leading cause of deaths in women worldwide. It is typically classified into the following three subtypes： estrogen receptor （ER）/progesterone receptor （PR）-positive （luminal）, human epidermal growth factor receptor 2 （HER2）-amplified, and ER/PR/HER2-triple negative BC （TNBC）. Tremendous progress has been made to understand molecular mechanisms underlying BC development, progression, and metastasis, and to develop molecule-targeted therapies for clinical applications.展开更多
Lung cancer remains the leading cause of cancer-related deaths worldwide.Despite the recent advances in cancer therapies,the 5-year survival of non-small cell lung cancer(NSCLC)patients hovers around 20%.Inherent and ...Lung cancer remains the leading cause of cancer-related deaths worldwide.Despite the recent advances in cancer therapies,the 5-year survival of non-small cell lung cancer(NSCLC)patients hovers around 20%.Inherent and acquired resistance to therapies(including radiation,chemotherapies,targeted drugs,and combination therapies)has become a significant obstacle in the successful treatment of NSCLC.c-Myc,one of the critical oncoproteins,has been shown to be heavily associated with the malignant cancer phenotype,including rapid proliferation,metastasis,and chemoresistance across multiple cancer types.The c-Myc proto-oncogene is amplified in small cell lung cancers(SCLCs)and overexpressed in over 50%of NSCLCs.c-Myc is known to actively regulate the tran-scription of cancer stemness genes that are recognized as major contributors to tumor progression and therapeutic resistance;thus,targeting c-Myc either directly or indirectly in mitigation of the cancer stemness phenotype be-comes a promising approach for development of a new strategy against drug resistant lung cancers.This review will summarize what is currently known about the mechanisms underlying c-Myc regulation of cancer stemness and its involvement in drug resistance and offer an overview on the current progress and future prospects in therapeutically targeting c-Myc in both SCLC and NSCLC.展开更多
Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidati...Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidation and reducing glutathione(GSH)levels,while it also inhibits ferroptosis by activating the expression of several ferroptosis repressors,such as FSP1 and iPLA2β,indicating the complexity of p53’s function in modulating ferroptosis in a cell-specific or context-specific manner(Liu and Gu,2022).展开更多
The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus...The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.展开更多
An accurate assessment of p53's functional statuses is critical for cancer genomic medicine.However,there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectab...An accurate assessment of p53's functional statuses is critical for cancer genomic medicine.However,there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing.These undetected cases are often misclassified as p53-normal,leading to inaccurate prognosis and downstream association analyses.To address this issue,we built the support vector machine(SVM)models to systematically reassess p53's functional statuses in TP53 wild-type(TP53^(WT))tumors from multiple The Cancer Genome Atlas(TCGA)cohorts.Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve(AUROC)of 0.9822,precision of 0.9747,and recall of 0.9784.Our study revealed that a significant proportion(87%-99%)of TP53^(WT) tumors actually had compromised p53 function.Additional analyses uncovered that these genetically intact but functionally impaired(termed as predictively reduced function of p53 or TP53^(WT)-pRF)tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors:heightened genomic instability and elevated levels of hypoxia.Clinically,patients with TP53^(WT)-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53(TP53^(WT)-pN)tumors,and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.展开更多
Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a ...Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress.In addition,these ribosomal proteins are involved in various physiological and pathological processes.This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins,as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis,immune signaling,and development.Wealso propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.展开更多
The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and...The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and metabolic changes, and leading to con- sequent suppression of tumour growth and progression. Because of the profoundly adverse effect of p53 on growth and prolifer- ation of cancer cells, several feedback mechanisms have been employed by the cells to constrain p53 activity. Two major antagonists MDM2 and MDMX （the long forms） are transcriptionally induced by p53, but in return block p53 activity, forming a negative feedback circuit and rendering chemoresistance of several cancer cells. However, they are not alone, as cancer cells also employ other proteins encoded by p53 target genes to inhibit p53 activity at transcriptional, translational, and posttransla- tional levels. This essay is thus composed to review a recent progress in understanding the mechanisms for how cancer cells hijack the p53 autoregulation by these proteins for their growth advantage and to discuss the clinical implications of these auto- regulatory loops.展开更多
Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is ...Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.展开更多
The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death,including apoptosis,through transcription-dependent and transcription-independent mechanisms.On the one hand,nuclear p53 ...The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death,including apoptosis,through transcription-dependent and transcription-independent mechanisms.On the one hand,nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes,such as NOXA,PUMA,BID,BAD,BIK,BAX,etc.,whereas it inactivates the expression of anti-apoptotic BCL-2,BCL-XL,and MCL1,leading to mitochondrial apoptosis.On the other hand,cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria.Apoptosis-related protein in TGF-βsignaling pathway(ARTS),a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene,triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli.We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress.ARTS in turn binds to p53,drives its mitochondrial localization,and enhances the interaction between p53 and BCL-XL,thereby promoting mitochondrial apoptosis.This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis,offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death,and discuss the clinical significance of ARTS in cancer and non-cancer diseases.展开更多
The tumor suppressor p53 plays an important role in the inhibition of cancer progression,particularly in response to chemotherapy or target-specific therapy.Inactivation or mutation of p53 often becomes a cancer’s ta...The tumor suppressor p53 plays an important role in the inhibition of cancer progression,particularly in response to chemotherapy or target-specific therapy.Inactivation or mutation of p53 often becomes a cancer’s tactic for drug resistance.One of the clinically applied therapeutic strategies is to inhibit poly(ADP-ribose)polymerase(PARP)activity,as PARP inhibitors are widely used for subsets of tumors with homologous recombination deficiency due to mutation of BRCA1/2 or other DNA repair-associated genes.It has been shown that p53 deficiency or mutation enhances the cytotoxicity of PARP inhibition in various tumors(Williamson et al.,2012).展开更多
The phiLosophy of Yin （阴） and Yang （阳） formed in ancient China describes a subtle, complementary, and sometimes intimate relationship between two opposites. This thousands of years old phil- osophy is, however, ...The phiLosophy of Yin （阴） and Yang （阳） formed in ancient China describes a subtle, complementary, and sometimes intimate relationship between two opposites. This thousands of years old phil- osophy is, however, perfectly suited to describe the relationship between p53 and MDM2, whose genes evolved hundreds of millions of years ago. p53 and MDM2 are found in both （some） invertebrate and （all） vertebrate organisms, and mutually live with and almost always depend on each other in most multi-cellular organisms, including humans.展开更多
Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functi...Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China （81302206 and 81560422）, the Development and Reform Commission of Jilin Province （2013C026-2）, and the Young Scholars Program of Norman Bethune Health Science Center of Jilin University （2013201012）, the Health and Family Planning Commission of Jiangxi Province （20143207） and the Natural Science Foundation of Jiangxi Province of China （20151BAB205016 and 20132BAB205008）.
文摘AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aido-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rvl cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family I member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family I member C3 enzyme activity and the inhibition of 22Rvl prostate cancer cell growth by decreasing the intfacellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKRlC3 inhibitors using berberine as the lead compound.
文摘The US Preventive Services Task Force （USPSTF） analyzed the benefits and harms of prostate specific antigen （PSA）- based screening for prostate cancer （PCa）. The Grade ＇D＇ recommendation of the USPSTF was based mainly on the Prostate, Lung, Colorectal, and Ovarian （PLCO） study in the United States. That result showed only a small reduction in PCa mortality. However, the data from the International Agency for Research on Cancer （IARC） iUustrated the PCa mortality rate （MR） decreased marked. To avoid the over-diagnosis and over-treatment, the American Cancer Society has changed its strategy and updated its guidance. The USPSTF neglected the aggressive PCa accounted for more then 30% of all PCa. Highly aggressive PCa can be diagnosed by PSA screening combined with Gleason grade. We hope that the USPSTF changes the ＇D＇ recommendation for PSA screening.
文摘The recent manuscript in New England Journal of Medicine by Antonarakis et al. has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 （AR-V7）, in circulating tumor cells （CTCs） from metastatic castrate-resistant prostate cancer （mCRPC） patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen （PSA） responses.
文摘The ability of epithelial neoplasms to evade both hormonal and cytotoxic therapies is self-evident as the common carcinomas （lung, stomach, breast, colon and prostate） at their metastatic stage are rarely curable with current therapies. Though the precise reasons for incurability are debated,
基金the following grants: National Institutes ofHealth/National Cancer Institute (NIH/NCI) RO1 CAI88609, Department of Defense W81XWH-15-1-0439, W81XWH-16-1-0317, and W81XWH-14-1-0485National Natural Science Foundation of China Project 81430087.
文摘The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
文摘The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myeloid cell differentiation. A small number of simple and complex variants of the classical t(15;17) have been reported. We report two complex three-way translocation variants,t(3;17;15)(q27;q21;q22) and t(8;17;15)(q24.3;q12;q22) in which the PML/RARA fusion gene has been created on the derivative 15 chromosomes. Many of these variant translocations are suspected by conventional cytogenetics but need to be confirmed with additional molecular testing. We discuss the importance of supplementing conventional cytogenetic testing with FISH and RT-PCR to accurately diagnose APL variant patients.
基金supported by grants from a DOD Career Development Award (CA140437)the Louisiana Clinical and Translational Science Center Pilot grants (U54GM104940 from NIH)+1 种基金a LSU LIFT2 funding, a NIH P20-GM121288-01 subproject, NIH RO1s (AI091526, AI128864, AI101046, and AI106676)the National Natural Science Foundation of China (81472547, 81400164, 81672924 and 81772930)
文摘Lipids are essential for mammalian cells to maintain many physiological functions. Emerging evidence has shown that cancer cells can develop specific alterations in lipid biosynthesis and metabolism to facilitate their survival and various malignant behaviors. To date, the precise role of cellular lipids and lipid metabolism in viral oncogenesis is still largely unclear with only a handful of literature covering this topic to implicate lipid metabolism in oncogenic virus associated pathogenesis. In this review, we focus on the role of lipid biosynthesis and metabolism in the pathogenesis of the Kaposi's sarcoma-associated herpesvirus, a common causative factor for cancers arising in the immunocompromised settings.
基金National Natural Science Foundation of China (81672566 and 81874053)National Natural Science Foundation of China (81702352)National Institutes of Health-National Cancer Institute grants (R01CA095441 and R01CA127724).
文摘Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called ‘gain-of-functions’(GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.
文摘Breast cancer （BC） is the most malignant cancer and the second leading cause of deaths in women worldwide. It is typically classified into the following three subtypes： estrogen receptor （ER）/progesterone receptor （PR）-positive （luminal）, human epidermal growth factor receptor 2 （HER2）-amplified, and ER/PR/HER2-triple negative BC （TNBC）. Tremendous progress has been made to understand molecular mechanisms underlying BC development, progression, and metastasis, and to develop molecule-targeted therapies for clinical applications.
基金H.L.was supported by NIH-NCI grants R01CA234605,R21CA272890,and U01CA252965,as well as the Reynolds and Ryan Families Endowed Chair fund and the Ladies Leukemia League fund.The figures and table were created using BioRender.com.
文摘Lung cancer remains the leading cause of cancer-related deaths worldwide.Despite the recent advances in cancer therapies,the 5-year survival of non-small cell lung cancer(NSCLC)patients hovers around 20%.Inherent and acquired resistance to therapies(including radiation,chemotherapies,targeted drugs,and combination therapies)has become a significant obstacle in the successful treatment of NSCLC.c-Myc,one of the critical oncoproteins,has been shown to be heavily associated with the malignant cancer phenotype,including rapid proliferation,metastasis,and chemoresistance across multiple cancer types.The c-Myc proto-oncogene is amplified in small cell lung cancers(SCLCs)and overexpressed in over 50%of NSCLCs.c-Myc is known to actively regulate the tran-scription of cancer stemness genes that are recognized as major contributors to tumor progression and therapeutic resistance;thus,targeting c-Myc either directly or indirectly in mitigation of the cancer stemness phenotype be-comes a promising approach for development of a new strategy against drug resistant lung cancers.This review will summarize what is currently known about the mechanisms underlying c-Myc regulation of cancer stemness and its involvement in drug resistance and offer an overview on the current progress and future prospects in therapeutically targeting c-Myc in both SCLC and NSCLC.
基金supported by the National Natural Science Foundation of China(82072879,82273098,81874053,82173022)General Program of Open Science Foundation of Jiangxi Cancer Hospital(2021J04)HL was in part funded by the Reynolds and Ryan Families Chair fund in Transitional Cancer at Tulane.
文摘Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidation and reducing glutathione(GSH)levels,while it also inhibits ferroptosis by activating the expression of several ferroptosis repressors,such as FSP1 and iPLA2β,indicating the complexity of p53’s function in modulating ferroptosis in a cell-specific or context-specific manner(Liu and Gu,2022).
文摘The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.
基金supported by the National Institutes of Health(Grant No.U10-CA180882-07)and the Mayo Clinic Center for Individualized Medicine,USA,as well as the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB38030400)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2019104),China.
文摘An accurate assessment of p53's functional statuses is critical for cancer genomic medicine.However,there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing.These undetected cases are often misclassified as p53-normal,leading to inaccurate prognosis and downstream association analyses.To address this issue,we built the support vector machine(SVM)models to systematically reassess p53's functional statuses in TP53 wild-type(TP53^(WT))tumors from multiple The Cancer Genome Atlas(TCGA)cohorts.Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve(AUROC)of 0.9822,precision of 0.9747,and recall of 0.9784.Our study revealed that a significant proportion(87%-99%)of TP53^(WT) tumors actually had compromised p53 function.Additional analyses uncovered that these genetically intact but functionally impaired(termed as predictively reduced function of p53 or TP53^(WT)-pRF)tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors:heightened genomic instability and elevated levels of hypoxia.Clinically,patients with TP53^(WT)-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53(TP53^(WT)-pN)tumors,and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.
基金H.L.was supported by NIH-NCI grants CA095441 and CA172468the Reynolds and Ryan Families chair fund.
文摘Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress.In addition,these ribosomal proteins are involved in various physiological and pathological processes.This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins,as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis,immune signaling,and development.Wealso propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.
基金H.L. was supported by NIH-NCl grants （RO1CA095441, ROlCA172468, R01CA127724, R21CA190775, and R21CA201889） as well as the Reynolds and Ryan Families Chair Fund. X.Z. was supported by the National Natural Science Foundation of China （no. 81672566）.
文摘The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and metabolic changes, and leading to con- sequent suppression of tumour growth and progression. Because of the profoundly adverse effect of p53 on growth and prolifer- ation of cancer cells, several feedback mechanisms have been employed by the cells to constrain p53 activity. Two major antagonists MDM2 and MDMX （the long forms） are transcriptionally induced by p53, but in return block p53 activity, forming a negative feedback circuit and rendering chemoresistance of several cancer cells. However, they are not alone, as cancer cells also employ other proteins encoded by p53 target genes to inhibit p53 activity at transcriptional, translational, and posttransla- tional levels. This essay is thus composed to review a recent progress in understanding the mechanisms for how cancer cells hijack the p53 autoregulation by these proteins for their growth advantage and to discuss the clinical implications of these auto- regulatory loops.
文摘Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.
基金supported by the National Natural Science Foundation of China(82072879 and 82273098 to X.Z.,82173022 to Q.H.,and 82060278 to J.C.)the Reynolds and Ryan Families Chair Fund in Transitional Cancer at Tulane to H.L.
文摘The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death,including apoptosis,through transcription-dependent and transcription-independent mechanisms.On the one hand,nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes,such as NOXA,PUMA,BID,BAD,BIK,BAX,etc.,whereas it inactivates the expression of anti-apoptotic BCL-2,BCL-XL,and MCL1,leading to mitochondrial apoptosis.On the other hand,cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria.Apoptosis-related protein in TGF-βsignaling pathway(ARTS),a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene,triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli.We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress.ARTS in turn binds to p53,drives its mitochondrial localization,and enhances the interaction between p53 and BCL-XL,thereby promoting mitochondrial apoptosis.This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis,offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death,and discuss the clinical significance of ARTS in cancer and non-cancer diseases.
文摘The tumor suppressor p53 plays an important role in the inhibition of cancer progression,particularly in response to chemotherapy or target-specific therapy.Inactivation or mutation of p53 often becomes a cancer’s tactic for drug resistance.One of the clinically applied therapeutic strategies is to inhibit poly(ADP-ribose)polymerase(PARP)activity,as PARP inhibitors are widely used for subsets of tumors with homologous recombination deficiency due to mutation of BRCA1/2 or other DNA repair-associated genes.It has been shown that p53 deficiency or mutation enhances the cytotoxicity of PARP inhibition in various tumors(Williamson et al.,2012).
文摘The phiLosophy of Yin （阴） and Yang （阳） formed in ancient China describes a subtle, complementary, and sometimes intimate relationship between two opposites. This thousands of years old phil- osophy is, however, perfectly suited to describe the relationship between p53 and MDM2, whose genes evolved hundreds of millions of years ago. p53 and MDM2 are found in both （some） invertebrate and （all） vertebrate organisms, and mutually live with and almost always depend on each other in most multi-cellular organisms, including humans.
基金H.L.and S.X.Z.were supported in part by NIH-NCI grants R01CA095441,R01CA234605,R01CA127724,as well as R21CA272890H.L.was also in part supported by the Reynolds and Ryan Families Endowed Chair fund and the NIH-NCI grant U01CA252965.
文摘Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.
