Oncotarget

Research Papers:

PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer

Yota Yasumizu, Hiroshi Hongo, Takeo Kosaka _, Shuji Mikami, Koshiro Nishimoto, Eiji Kikuchi and Mototsugu Oya

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:27698-27707. https://doi.org/10.18632/oncotarget.25498

Metrics: PDF 1242 views  |   HTML 1310 views  |   ?  


Abstract

Yota Yasumizu1,*, Hiroshi Hongo1,*, Takeo Kosaka1,*, Shuji Mikami2, Koshiro Nishimoto3, Eiji Kikuchi1 and Mototsugu Oya1

1Department of Urology, Keio University School of Medicine, Tokyo, Japan

2Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan

3Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Japan

*These authors have contributed equally to this work

Correspondence to:

Takeo Kosaka, email: takemduro@gmail.com

Keywords: CRPC; PKM2; PI3K-Akt-mTOR signaling pathways; hypoxias; C4-2AT6

Received: June 04, 2017    Accepted: May 07, 2018    Published: June 12, 2018

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25498