Abstract
The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC.
Highlights
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer related death in the United States [1, 2]
We demonstrated the resistance of C4-2AT6 under hypoxia to PI3K/Akt/mTOR inhibitor, and the possibility of Pyruvate kinase M2 (PKM2) involving to the resistance of mTOR inhibitor
Our results suggested that high PKM2 expression was related to shorter PSA recurrence-free survival
Summary
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer related death in the United States [1, 2]. Most metastatic prostate cancer acquire androgen independent growth ability and show resistance to androgen deprivation therapy (ADT) [3]. This is so-called castration-resistant prostate cancer (CRPC). Recently other novel drugs have shown promising results in prolonging survival, including the cytochrome P17 inhibitor abiraterone acetate, the anti-androgen enzalutamide, cytotoxic drug cabazitaxel, and the bone-targeting radiopharmaceutical radium-223 dichloride leading to approval in Japan [4, 5, 6, 7, 8]. The further investigation about CRPC is needed to establish a new treatment strategy for CRPC
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