Adenosine triphosphate(ATP)-citrate lyase(ACLY)converts cytosolic citrate from the tricarboxylic acid cycle(TCA cycle)into acetyl coenzyme A(acetyl-CoA),which is a building block for cholesterol and fatty acid synthes...Adenosine triphosphate(ATP)-citrate lyase(ACLY)converts cytosolic citrate from the tricarboxylic acid cycle(TCA cycle)into acetyl coenzyme A(acetyl-CoA),which is a building block for cholesterol and fatty acid synthesis.Abnormally high expression of ACLY is associated with multiple metabolic diseases including dyslipidemia,atherosclerosis and non-alcoholic steatohepatitis(NASH),making ACLY an appealing target.In previous work,326Eb was discovered,featuring an alkenyl dicarboxylic acid scaffold as a novel ACLY inhibitor.326E can be potentially used to treat hypercholesterolemia and is currently undergoing phase II clinical trials.In this study,a series of diacids containing conjugated diene were developed based on impurities in manufacturing process of 326E in good manufacturing practice of medical products(GMP)condition,which represented a unique structural type different from known ACLY inhibitors.Among synthesized all eight possible isomers,compounds 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro and 43ZZ showed favorable pharmacokinetics.Furthermore,oral administration of 43ZZ and 52EE demonstrated a marked reduction of hepatic lipogenesis,along with lowered plasma levels of triglyceride and cholesterol,thereby confirming that these diene diacids as novel ACLY inhibitors have therapeutic potential for hyperlipidemia.展开更多
Chromatin remodeling critically influences gene ex-pression and contributes to chemotherapy resis-tance in cancer.We introduce two Pt-based adenosine triphosphate citrate lyase(ACLY)inhibi-tors,PSN and PDN,which induc...Chromatin remodeling critically influences gene ex-pression and contributes to chemotherapy resis-tance in cancer.We introduce two Pt-based adenosine triphosphate citrate lyase(ACLY)inhibi-tors,PSN and PDN,which induce chromatin compac-tion to counter cisplatin(CDDP)resistance.PDN displayed significant cytotoxicity against CDDP-resistant cancer cells and demonstrated potent in vivo anticancer activity upon oral dosing with mini-mal toxicity.Mechanistically,PDN efficiently entered cancer cells,inducing DNA damage,downregulating ACLY,inhibiting DNA damage-induced histone acetylation,promoting chromatin compaction,and consequently suppressing genes linked to CDDP re-sistance.PDN,an oral metal-based ACLY inhibitor,represents a pioneering approach in conquering chemoresistance via chromatin remodeling,offering new insights for designing next-generation antican-cer metallodrugs.展开更多
To the editor:ATP-citrate lyase(ACLY)is the key enzyme linking glucose catabolism to lipogenesis.Targeting hepatic ACLY for lowering low density lipoprotein-cholesterol(LDL-C)and attenuating atherosclerosis has been v...To the editor:ATP-citrate lyase(ACLY)is the key enzyme linking glucose catabolism to lipogenesis.Targeting hepatic ACLY for lowering low density lipoprotein-cholesterol(LDL-C)and attenuating atherosclerosis has been validated in preclinical animal models and hypercholesterolemic patients1.Bempedoic acid(ETC1002),a first-in-class,potent and orally bioavailable inhibitor of ACLY,has been approved by the US FDA to reduce cardiovascular risk in patients who do not achieve their recommended LDL-C levels through other means.展开更多
Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis.Here,we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arth...Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis.Here,we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis(RA).Among them,decreased expression of RNA binding motif protein 25(RBM25)was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages.Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes(including Il1b,Il6,and Cxcl10)was coupled with histone 3 lysine 9 acetylation(H3K9ac)and H3K27ac modifications as well as hypoxia inducible factor-1α(HIF-1α)activity.Furthermore,RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase(Acly)pre-mRNA,resulting in two distinct Acly isoforms,Acly Long(Acly L)and Acly Short(Acly S).In proinflammatory macrophages,Acly L was subjected to protein lactylation on lysine 918/995,whereas Acly S did not,which influenced its affinity for metabolic substrates and subsequent metabolic activity.RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform,enhancing glycolysis and acetyl-CoA production for epigenetic remodeling,macrophage overactivation and tissue inflammatory injury.Finally,macrophage-specific deletion of RBM25 led to inflammaging,including spontaneous arthritis in various joints of mice and inflammation in multiple organs,which could be relieved by pharmacological inhibition of Acly.Overall,targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.展开更多
To investigate the impact of hyperglycemia on the prognosis of patients with gastric cancer and identify key molecules associated with high glucose levels in gastric cancer development,RNA sequencing data and clinical...To investigate the impact of hyperglycemia on the prognosis of patients with gastric cancer and identify key molecules associated with high glucose levels in gastric cancer development,RNA sequencing data and clinical features of gastric cancer patients were obtained from The Cancer Genome Atlas(TCGA)database.High glucose-related genes strongly associated with gastric cancer were identified using weighted gene co-expression network and differential analyses.A gastric cancer prognosis signature was constructed based on these genes and patients were categorized into high-and low-risk groups.The immune statuses of the two patient groups were compared.ATP citrate lyase(ACLY),a gene significantly related to the prognosis,was found to be upregulated upon high-glucose stimulation.Immunohistochemistry and molecular analyses confirmed high ACLY expression in gastric cancer tissues and cells.Gene Set Enrichment Analysis(GSEA)revealed the involvement of ACLY in cell cycle and DNA replication processes.Inhibition of ACLY affected the proliferation and migration of gastric cancer cells induced by high glucose levels.These findings suggest that ACLY,as a high glucose-related gene,plays a critical role in gastric cancer progression.展开更多
Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cyto...Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.展开更多
Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional stu...Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.展开更多
ATP citrate lyase(ACLY)synthesizes cytosolic acetyl coenzyme A(acetyl-CoA),an essential biosynthetic precursor for lipid synthesis and the acetyl donor required for protein acetylation.The aberrant expression and acti...ATP citrate lyase(ACLY)synthesizes cytosolic acetyl coenzyme A(acetyl-CoA),an essential biosynthetic precursor for lipid synthesis and the acetyl donor required for protein acetylation.The aberrant expression and activity of ACLY has been documented in multiple human cancers.ETC-1002 is an indirect ACLY inhibitor,and it has recently been approved by the FDA as an additional therapeutic option in high-risk hypercholesterolemia patients unable to meet goals with standard therapy.In this work,we identified a series of novel long-chain alkenyl diacids as potent direct ACLY inhibitors,and comprehensive structure-activity relationship analysis showed that compound 18f was the most potent ACLY inhibitor with an IC50 value of 1.5μmol/L.Subsequent ester formation of 18f gave a new series of compounds such as 25f that maintained ACLY inhibitory activity and improved antitumor cell proliferation effects.展开更多
Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-nam...Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.展开更多
Background: Autophagy is elevated in metastatic tumors and is often associatedwith active epithelial-to-mesenchymal transition (EMT). However, the extent towhich EMT is dependent on autophagy is largely unknown. This ...Background: Autophagy is elevated in metastatic tumors and is often associatedwith active epithelial-to-mesenchymal transition (EMT). However, the extent towhich EMT is dependent on autophagy is largely unknown. This study aimed toidentify the mechanisms by which autophagy facilitates EMT.Methods: We employed a liquid chromatography-based metabolomic approachwith kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1)gene co-mutated (KL) cells that represent an autophagy/EMT-coactivatedinvasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-drivenEMT activation were further investigated by quantitative real-time polymerasechain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation,immunofluorescence staining, and metabolite assays. The effects of chemicaland genetic perturbations on autophagic flux were assessed by two orthogonalapproaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnoveranalysis by Western blotting and monomeric red fluorescent protein-greenfluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenchingassay. Transcription factor EB (TFEB) activity was measured by coordinatedlysosomal expression and regulation (CLEAR) motif-driven luciferase reporterassay. Experimental metastasis (tail vein injection) mouse models were used toevaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2(CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVISluciferase imaging system.Results: We found that autophagy in KL cancer cells increased acetyl-coenzymeA (acetyl-CoA), which facilitated the acetylation and stabilization of theEMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetylSnail axis was further validated in tumor tissues and in autophagy-activatedpancreatic cancer cells. TFEB acetylation in KL cancer cells sustained prometastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KLcancer cells in vivo.Conclusions: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRASLKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetylCoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potentialtherapeutic strategy to suppress metastasis of KL lung cancer.展开更多
文摘Adenosine triphosphate(ATP)-citrate lyase(ACLY)converts cytosolic citrate from the tricarboxylic acid cycle(TCA cycle)into acetyl coenzyme A(acetyl-CoA),which is a building block for cholesterol and fatty acid synthesis.Abnormally high expression of ACLY is associated with multiple metabolic diseases including dyslipidemia,atherosclerosis and non-alcoholic steatohepatitis(NASH),making ACLY an appealing target.In previous work,326Eb was discovered,featuring an alkenyl dicarboxylic acid scaffold as a novel ACLY inhibitor.326E can be potentially used to treat hypercholesterolemia and is currently undergoing phase II clinical trials.In this study,a series of diacids containing conjugated diene were developed based on impurities in manufacturing process of 326E in good manufacturing practice of medical products(GMP)condition,which represented a unique structural type different from known ACLY inhibitors.Among synthesized all eight possible isomers,compounds 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro and 43ZZ showed favorable pharmacokinetics.Furthermore,oral administration of 43ZZ and 52EE demonstrated a marked reduction of hepatic lipogenesis,along with lowered plasma levels of triglyceride and cholesterol,thereby confirming that these diene diacids as novel ACLY inhibitors have therapeutic potential for hyperlipidemia.
基金the National Key R&D Program of China(grant no.2019YFA09006600)National Natural Science Foundation of China(grant nos.22293050,22293051,21977048,92053111,92153303,21731004,91953201,22107047)+3 种基金Natural Science Foundation of Jiangsu Province(grant no.BK20202004)Fundamental Research Funds for the Central Universities(grant no.0205/14380225)Jiangsu Specially-Appointed Professor Plan,Program for Innovative Talents and Entrepreneur in Jiangsu,Postdoctoral Research Funding Program of Jiangsu Province(grant no.003503)Excellent Research Program of Nanjing University(grant no.ZYJH004).
文摘Chromatin remodeling critically influences gene ex-pression and contributes to chemotherapy resis-tance in cancer.We introduce two Pt-based adenosine triphosphate citrate lyase(ACLY)inhibi-tors,PSN and PDN,which induce chromatin compac-tion to counter cisplatin(CDDP)resistance.PDN displayed significant cytotoxicity against CDDP-resistant cancer cells and demonstrated potent in vivo anticancer activity upon oral dosing with mini-mal toxicity.Mechanistically,PDN efficiently entered cancer cells,inducing DNA damage,downregulating ACLY,inhibiting DNA damage-induced histone acetylation,promoting chromatin compaction,and consequently suppressing genes linked to CDDP re-sistance.PDN,an oral metal-based ACLY inhibitor,represents a pioneering approach in conquering chemoresistance via chromatin remodeling,offering new insights for designing next-generation antican-cer metallodrugs.
基金supported by grants from the National Key R&D Program of China(Grant No.2021YFC2500500)the National Natural Science Foundation of China(Grant Nos.82370444,82070464,12411530127)+1 种基金supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02,China)Anhui Provincial Natural Science Foundation(Grant No.2208085J08,China).
文摘To the editor:ATP-citrate lyase(ACLY)is the key enzyme linking glucose catabolism to lipogenesis.Targeting hepatic ACLY for lowering low density lipoprotein-cholesterol(LDL-C)and attenuating atherosclerosis has been validated in preclinical animal models and hypercholesterolemic patients1.Bempedoic acid(ETC1002),a first-in-class,potent and orally bioavailable inhibitor of ACLY,has been approved by the US FDA to reduce cardiovascular risk in patients who do not achieve their recommended LDL-C levels through other means.
基金supported by the National Key Research&Development Program of China(2023YFC2307302,2019YFA0801502,2023YFC2307001,2023YFC2307002)the National Natural Science Foundation of China(82071790,82070415,82271797,82341065,82371825,32400727,82201955)+1 种基金the program of Shanghai outstanding academic leader in public health subject(GWVI-11.2-XD29)the experimental animal program sponsored by the Science and Technology Commission of Shanghai Municipality(23141902300).
文摘Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis.Here,we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis(RA).Among them,decreased expression of RNA binding motif protein 25(RBM25)was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages.Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes(including Il1b,Il6,and Cxcl10)was coupled with histone 3 lysine 9 acetylation(H3K9ac)and H3K27ac modifications as well as hypoxia inducible factor-1α(HIF-1α)activity.Furthermore,RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase(Acly)pre-mRNA,resulting in two distinct Acly isoforms,Acly Long(Acly L)and Acly Short(Acly S).In proinflammatory macrophages,Acly L was subjected to protein lactylation on lysine 918/995,whereas Acly S did not,which influenced its affinity for metabolic substrates and subsequent metabolic activity.RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform,enhancing glycolysis and acetyl-CoA production for epigenetic remodeling,macrophage overactivation and tissue inflammatory injury.Finally,macrophage-specific deletion of RBM25 led to inflammaging,including spontaneous arthritis in various joints of mice and inflammation in multiple organs,which could be relieved by pharmacological inhibition of Acly.Overall,targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.
基金supported by grants from the Natural Science Foundation of Hebei Province(No.C2021206011)Beijing-Tianjin-Hebei Collaborative Innovation Community Construction Project(22347702D).
文摘To investigate the impact of hyperglycemia on the prognosis of patients with gastric cancer and identify key molecules associated with high glucose levels in gastric cancer development,RNA sequencing data and clinical features of gastric cancer patients were obtained from The Cancer Genome Atlas(TCGA)database.High glucose-related genes strongly associated with gastric cancer were identified using weighted gene co-expression network and differential analyses.A gastric cancer prognosis signature was constructed based on these genes and patients were categorized into high-and low-risk groups.The immune statuses of the two patient groups were compared.ATP citrate lyase(ACLY),a gene significantly related to the prognosis,was found to be upregulated upon high-glucose stimulation.Immunohistochemistry and molecular analyses confirmed high ACLY expression in gastric cancer tissues and cells.Gene Set Enrichment Analysis(GSEA)revealed the involvement of ACLY in cell cycle and DNA replication processes.Inhibition of ACLY affected the proliferation and migration of gastric cancer cells induced by high glucose levels.These findings suggest that ACLY,as a high glucose-related gene,plays a critical role in gastric cancer progression.
基金supported by grants from the National Natural Science Foundation of China(92057116 and 82170872)the Medical Guidance Project of Shanghai Science and Technology Commission(20S11903400,China)+3 种基金the“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040328,China)the“State Key Laboratory of Drug Research”Shanghai Institute of Materia Medica,Chinese Academy of Sciences(SIMM2105KF-02,China)Natural Science Foundation of Shanghai’s 2021“Science and Technology Innovation Action Plan”(21ZR1475300,China)the Lingang Laboratory(LG-QS-202205-01,China)。
文摘Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.
基金This manuscript has been partially supported by NIH/NCI grants R00CA160638 and R01CA245699(H.L.),and Supple-ment for Diversity(V.A.),T32 CA080621-15(R.T.),and R01CA213843(R.A.K),American Cancer Society grant ACS127951-RSG-15-025-01-CSM(H.L.)the Susan G.Komen Foundation CCR15332826(H.L.)and CCR18548501(X.L.)+3 种基金the Department of Defense W81XWH-16-1-0021(H.L.)the Lynn Sage Cancer Research Foundation(X.L.and H.L.)North-western University’s Endocrinology Training Grant T32DK007169-39(A.H.)and start-up funds fromCaseWestern Reserve University and at Northwestern University(H.L.).
文摘Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.
基金supported by grants fromthe"Personalized Medicines-Molecular Signature-based Drug Discovery and Development"Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040328)the Medical Guidance Project of Shanghai ScienceandTechnology Commission(20S11903400)+1 种基金the Natural Science Foundation of Shanghai's 2021"Science and Technology InnovationAction Plan"(21ZR1475300)the National Natural Science Foundation of China(No.82170872).
文摘ATP citrate lyase(ACLY)synthesizes cytosolic acetyl coenzyme A(acetyl-CoA),an essential biosynthetic precursor for lipid synthesis and the acetyl donor required for protein acetylation.The aberrant expression and activity of ACLY has been documented in multiple human cancers.ETC-1002 is an indirect ACLY inhibitor,and it has recently been approved by the FDA as an additional therapeutic option in high-risk hypercholesterolemia patients unable to meet goals with standard therapy.In this work,we identified a series of novel long-chain alkenyl diacids as potent direct ACLY inhibitors,and comprehensive structure-activity relationship analysis showed that compound 18f was the most potent ACLY inhibitor with an IC50 value of 1.5μmol/L.Subsequent ester formation of 18f gave a new series of compounds such as 25f that maintained ACLY inhibitory activity and improved antitumor cell proliferation effects.
基金support from the National Natural Science Foundation of China(22237007 and 22177122)the Biological Resources Program of Chinese Academy of Sciences(CAS)(KFJ-BRP-008-001)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022282)is gratefully acknowledged.We thank Prof.Shi-Man Huang,Department of Biology,Hainan University,China,for the identification of the plant material.
文摘Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.
基金Korea Health Technology R&D Project through the Korea Health Industry Development Institute,Grant/Award Number:HI14C1324National Research Foundation of Korea,Grant/Award Numbers:2020R1A2C3007792,2019R1A2C3004155,2019H1A2A1075632+2 种基金NCI Lung Cancer SPORE,Grant/Award Number:P50CA70907Cancer Prevention and Research Institute of Texas(CPRIT),Grant/Award Number:RP160652“Team Science Award”of Yonsei University College of Medicine,Grant/Award Number:6-2021-0194。
文摘Background: Autophagy is elevated in metastatic tumors and is often associatedwith active epithelial-to-mesenchymal transition (EMT). However, the extent towhich EMT is dependent on autophagy is largely unknown. This study aimed toidentify the mechanisms by which autophagy facilitates EMT.Methods: We employed a liquid chromatography-based metabolomic approachwith kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1)gene co-mutated (KL) cells that represent an autophagy/EMT-coactivatedinvasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-drivenEMT activation were further investigated by quantitative real-time polymerasechain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation,immunofluorescence staining, and metabolite assays. The effects of chemicaland genetic perturbations on autophagic flux were assessed by two orthogonalapproaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnoveranalysis by Western blotting and monomeric red fluorescent protein-greenfluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenchingassay. Transcription factor EB (TFEB) activity was measured by coordinatedlysosomal expression and regulation (CLEAR) motif-driven luciferase reporterassay. Experimental metastasis (tail vein injection) mouse models were used toevaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2(CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVISluciferase imaging system.Results: We found that autophagy in KL cancer cells increased acetyl-coenzymeA (acetyl-CoA), which facilitated the acetylation and stabilization of theEMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetylSnail axis was further validated in tumor tissues and in autophagy-activatedpancreatic cancer cells. TFEB acetylation in KL cancer cells sustained prometastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KLcancer cells in vivo.Conclusions: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRASLKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetylCoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potentialtherapeutic strategy to suppress metastasis of KL lung cancer.
