Login to Access Video or Poster Abstract: MP98-16
Sources of Funding: VA

Introduction

Chemoresistance to cisplatin is a principal cause of treatment failure and disease progression of advanced bladder cancer. In the present study we explore the novel relationship between cisplatin resistance and pyruvate kinase 2 (PKM2) – a rate-limiting enzyme responsible for Warburg effect in cancer cells, and whether down-regulating PKM2 by RNAi or small molecules reduces chemoresistance and enhances chemosensitivity of bladder cancer cells to cisplatin.

Methods

Cell lines from mouse and human bladder cancer and their derivatives expressing RNAi of PKM2 were assessed for their chemosensitivity to cisplatin or shikonin - a chemical inhibitor of PKM2, or both. The effects and mechanisms of PKM2 inhibition on cisplatin-resistance were examined. Cisplatin and shikonin as single or dual agents for inhibiting bladder cancer proliferation and metastasis were further tested in syngeneic mice.

Results

Shikonin binds PKM2 and inhibits bladder cancer cell proliferation 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 growth inhibition and apoptosis than when used alone. Experimentally 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 bladder cancer growth and lung metastases.

Conclusions

PKM2 overexpression is a key mechanism of natural and acquired chemoresistance of bladder cancer 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 bladder cancer.

Funding

VA