Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative bre...Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.展开更多
三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学...三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。展开更多
Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its liga...Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.展开更多
Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and...Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.展开更多
Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side ...Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.展开更多
Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autoph...Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.展开更多
[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previ...[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previous in vitro activity screening,the most active acetylenic phenols were selected for further analysis.Genes associated with triple-negative breast cancer(TNBC)were retrieved from the GAD and OMIM databases.Using Cytoscape software,a compound-target-pathway interaction network was constructed to visualize the relationships between the acetylenic phenols,their potential targets,and related pathways.Functional enrichment analysis of GO terms and KEGG pathways was performed using the DAVID database to identify key signaling mechanisms.Furthermore,molecular docking was conducted to evaluate the binding interactions between the acetylenic phenols and the potential core targets.[Results]Acetylenic phenols exhibit potential anticancer effects by modulating multiple signaling pathways,including the PI3K-Akt pathway,cell cycle pathway,and breast cancer pathway,which are closely associated with the pathophysiological processes of triple-negative breast cancer(TNBC)such as cell proliferation,apoptosis,and cell cycle regulation.Molecular docking results indicated that acetylenic phenols bind effectively to their targets via hydrogen bonding,hydrophobic interactions,andπ-stacking,indicating strong binding affinity.[Conclusions]Acetylenic phenols exert anti-TNBC effects by modulating key targets,including EGFR,RAF1,ESR1,CHEK1,and CDC25C,and influencing associated signaling pathways.These findings reveal the molecular mechanism underlying their anti-TNBC activity and provide a theoretical foundation for the potential application of acetylenic phenols in TNBC treatment.展开更多
The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research ...The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research indicates the aberrant expression of diverse tyrosine kinases(TKs)within this cancer,contributing significantly to tumor cell proliferation,survival,invasion,and migration.The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies,given their pivotal roles in tumor initiation,progression,and advancement.Intensive investigations have focused on various monoclonal antibodies(mAbs)and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor(EGFR),vascular endothelial growth factor(VEGF),vascular endothelial growth factor receptor(VEGFR),cellular mesenchymal-epithelial transition factor(c-MET),human epidermal growth factor receptor 2(HER2),among others,for combating TNBC.These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents.Despite these advances,a substantial terrain of unexplored potential lies within the realm of TK-targeted therapeutics,which hold promise in reshaping the therapeutic landscape.This review summarizes the various TK-targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC,dissecting the outcomes and revelations stemming from diverse clinical investigations.A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBC for the maximum efficiency of TK-targeted therapeutics,either as standalone treatments or a combination.Moreover,our observation highlights that the outcomes of TK-targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort,emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.展开更多
Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study ...Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.展开更多
Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits syntheti...Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.展开更多
基金the projects of the National Key Research and Development Program(No.2021YFA0716702)the National Natural Science Foundation of China(Nos.61805122,22022404 and 22074050)+5 种基金Green Industry Science and Technology Leading Project of Hubei University of Technology(No.XJ2021003301)the National Natural Science Foundation of Hubei Province(No.2022CFA033)supported by Chinese Society of Clinical Oncology(CSCO)supported by Jiangsu Hengrui Cancer Research Foundation(No.YHR2019–0325)supported by the Fundamental Research Funds for the Central Universities(No.CCNU22QN007)supported by the Opening Fund from the Jiangsu Key Laboratory of Medical Optics,Suzhou Institute of Biomedical Engineering and Technology(No.JKLMO202203)supported by the Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,MO(No.M2022–5).
文摘Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.
文摘三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。
基金supported by the Department of Science and Technology(Nano Mission:DST/NM/NT/2018/105(G),SERB:EMR/2017/000992/HS&EMR/2017/001183)Council of Scientific and Industrial Research[(FBR Project No.31-2(274)2020e21),HCP-40],Govt.of India.
文摘Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.
基金The study was supported by Ovarian Cancer Research Alliance and the Johns Hopkins-Allegheny Health Network Cancer Research Fund,United States.
文摘Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.
基金the Xuzhou Science and Technology Bureau,No.KC23186,Jiangsu Provincial Key Laboratory of New Drug Research and Clinical Pharmacy Project(No.XZSYSKF2023013)Key Medical Disciplines of Jiangsu Province’s 14th Five-Year Plan(ZDXK202237).
文摘Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.
基金the National Natural Science Foundation of China(Nos.22307009,82374155,82073997,82104376)the Sichuan Science and Technology Program(Nos.2023NSFSC1108,2024NSFTD0023)+1 种基金the Postdoctoral Research Project of Sichuan Provincethe Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
文摘Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.
基金Supported by General Program of Natural Science Foundation of Sichuan Province(2024NSFSC0706)Program of Sichuan Administration of Traditional Chinese Medicine(25MSZX326)+1 种基金Research Initiation Fund for High-level Talents of Sichuan College of Traditional Chinese Medicine(24ZRBS05)School-level Project of Sichuan College of Traditional Chinese Medicine(24SD02).
文摘[Objectives]To investigate the anti-tumor molecular mechanism of acetylenic phenols against triple-negative breast cancer(TNBC)using network pharmacology and molecular docking approaches.[Methods]Based on team s previous in vitro activity screening,the most active acetylenic phenols were selected for further analysis.Genes associated with triple-negative breast cancer(TNBC)were retrieved from the GAD and OMIM databases.Using Cytoscape software,a compound-target-pathway interaction network was constructed to visualize the relationships between the acetylenic phenols,their potential targets,and related pathways.Functional enrichment analysis of GO terms and KEGG pathways was performed using the DAVID database to identify key signaling mechanisms.Furthermore,molecular docking was conducted to evaluate the binding interactions between the acetylenic phenols and the potential core targets.[Results]Acetylenic phenols exhibit potential anticancer effects by modulating multiple signaling pathways,including the PI3K-Akt pathway,cell cycle pathway,and breast cancer pathway,which are closely associated with the pathophysiological processes of triple-negative breast cancer(TNBC)such as cell proliferation,apoptosis,and cell cycle regulation.Molecular docking results indicated that acetylenic phenols bind effectively to their targets via hydrogen bonding,hydrophobic interactions,andπ-stacking,indicating strong binding affinity.[Conclusions]Acetylenic phenols exert anti-TNBC effects by modulating key targets,including EGFR,RAF1,ESR1,CHEK1,and CDC25C,and influencing associated signaling pathways.These findings reveal the molecular mechanism underlying their anti-TNBC activity and provide a theoretical foundation for the potential application of acetylenic phenols in TNBC treatment.
基金supported by the Department of Biotechnology(DBT),Government of India(BT/556/NE/U-Excel/).
文摘The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer(TNBC).Recent research indicates the aberrant expression of diverse tyrosine kinases(TKs)within this cancer,contributing significantly to tumor cell proliferation,survival,invasion,and migration.The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies,given their pivotal roles in tumor initiation,progression,and advancement.Intensive investigations have focused on various monoclonal antibodies(mAbs)and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor(EGFR),vascular endothelial growth factor(VEGF),vascular endothelial growth factor receptor(VEGFR),cellular mesenchymal-epithelial transition factor(c-MET),human epidermal growth factor receptor 2(HER2),among others,for combating TNBC.These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents.Despite these advances,a substantial terrain of unexplored potential lies within the realm of TK-targeted therapeutics,which hold promise in reshaping the therapeutic landscape.This review summarizes the various TK-targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC,dissecting the outcomes and revelations stemming from diverse clinical investigations.A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBC for the maximum efficiency of TK-targeted therapeutics,either as standalone treatments or a combination.Moreover,our observation highlights that the outcomes of TK-targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort,emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.
文摘Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.
基金supported by the National Natural Science Foundation of China to Jinhua Zhou(Nos.82172609)Jiangsu Social Development Project(Nos.BE2022729).
文摘Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.
