Abstract
The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant 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.
| Original language | English |
|---|---|
| Pages (from-to) | 27698-27707 |
| Number of pages | 10 |
| Journal | Oncotarget |
| Volume | 9 |
| Issue number | 45 |
| DOIs | |
| Publication status | Published - 2018 Jun 12 |
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Keywords
- C4-2AT6
- CRPC
- Hypoxias
- PI3K-Akt-mTOR signaling pathways
- PKM2
ASJC Scopus subject areas
- Oncology
Cite this
PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer. / Yasumizu, Yota; Hongo, Hiroshi; Kosaka, Takeo; Mikami, Shuji; Nishimoto, Koshiro; Kikuchi, Eiji; Oya, Mototsugu.
In: Oncotarget, Vol. 9, No. 45, 12.06.2018, p. 27698-27707.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer
AU - Yasumizu, Yota
AU - Hongo, Hiroshi
AU - Kosaka, Takeo
AU - Mikami, Shuji
AU - Nishimoto, Koshiro
AU - Kikuchi, Eiji
AU - Oya, Mototsugu
PY - 2018/6/12
Y1 - 2018/6/12
N2 - The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant 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.
AB - The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant 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.
KW - C4-2AT6
KW - CRPC
KW - Hypoxias
KW - PI3K-Akt-mTOR signaling pathways
KW - PKM2
UR - http://www.scopus.com/inward/record.url?scp=85048372828&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048372828&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25498
DO - 10.18632/oncotarget.25498
M3 - Article
AN - SCOPUS:85048372828
VL - 9
SP - 27698
EP - 27707
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 45
ER -