title: Inhibition of Pyruvate Kinase M2 Markedly Reduces Chemoresistance of Advanced Bladder Cancer to Cisplatin.
abstract: Chemoresistance to cisplatin is a principal cause of treatment failure and mortality of advanced bladder cancer (BC). The underlying mechanisms remain unclear, which hinders the development of preventive strategies. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC. This study explores the role of PKM2 in chemoresistance and whether inhibiting PKM2 augments the chemosensitivity to cisplatin and reduces BC growth and progression. We found that Shikonin binds PKM2 and inhibits BC cell survival in a dose-dependent but pyruvate kinase activity-independent manner. Down-regulation of PKM2 by shRNA blunts cellular responses to shikonin but enhances the responses to cisplatin. Shikonin and cisplatin together exhibit significantly greater inhibition of proliferation and apoptosis than when used alone. Induced cisplatin-resistance is strongly associated with PKM2 overexpression, and cisplatin-resistant cells respond sensitively to shikonin. In syngeneic mice, shikonin and cisplatin together, but not as single-agents, markedly reduces BC growth and metastasis. Based on these data, we conclude that PKM2 overexpression is a key mechanism of chemoresistance of advanced BC to cisplatin. Inhibition of PKM2 via RNAi or chemical inhibitors may be a highly effective approach to overcome chemoresistance and improve the outcome of advanced BC.
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.|Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.|Veterans Affairs New York Harbor Healthcare System Manhattan Campus, New York, NY 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000378:metabolism; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D058105:Polymerization; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: D000199:Actins; D009285:Naphthoquinones; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C016101:shikonin; D011770:Pyruvate Kinase; D002945:Cisplatin