title: Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells.
abstract: Ursolic acid (UA) has shown the anti-tumor properties against a number of human cancers both in vivo and in vitro, however, its effect in bladder cancer and the corresponding mechanisms of action remain largely unknown. Here we found that UA dose-dependently induced growth inhibition and apoptosis in human bladder cancer T24 cells, and activation of AMP-activated protein kinase (AMPK) may contribute to the process. Our Western-blot results demonstrated a significant AMPK activation after UA treatment in T24 cells. Notably, knockdown of AMPKα by the targeted shRNA largely inhibited UA-induced T24 cell growth inhibition and apoptosis, while an AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) or a constitutively active form of AMPK mimic UA's effect. We found the ceramide level was increased after UA treatment in T24 cells, and UA-induced AMPK activation and T24 cell apoptosis were inhibited by ceramide synthase inhibitor fumonisin B1, and was enhanced by exogenously adding cell permeable short-chain ceramide (C6), suggesting that ceramide might serve as an upstream signal for AMPK activation. Further, activation of AMPK by UA promoted c-Jun N-terminal kinase (JNK) activation, but inhibited mTOR complex 1 (mTORC1) signaling to cause survivin down-regulation. Our study suggests that activation of AMPK by UA contributes to growth inhibition and apoptosis in human bladder cancer cells.
authors.affiliation: Department of Urology, The Military General Hospital of Beijing PLA, Beijing 100700, China. qingyouzheng@yahoo.com
authors.forename: Qing-you
authors.initials: QY
authors.lastname: Zheng
authors.forename: Feng-suo
authors.initials: FS
authors.lastname: Jin
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Guo-hui
authors.initials: GH
authors.lastname: Zhang
authors.forename: Xing
authors.initials: X
authors.lastname: Ai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology*; D000097245:Ursolic Acid
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D000972:Antineoplastic Agents, Phytogenic; D048031:JNK Mitogen-Activated Protein Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C526180:PRKAA1 protein, human; C031143:AICA ribonucleotide