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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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

Yota Yasumizu1, Hiroshi Hongo1, Takeo Kosaka1

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

Oncotarget
|July 3, 2018
PubMed

Insights

Hypoxia increases resistance to mTOR inhibitors in castration-resistant prostate cancer (CRPC) by upregulating Pyruvate Kinase M2 (PKM2). Targeting PKM2 may overcome this resistance and improve therapeutic outcomes in CRPC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate cancer, particularly castration-resistant prostate cancer (CRPC), often exhibits elevated PI3K/Akt/mTOR pathway signaling.
  • Hypoxia is a common feature in aggressive tumors and can influence treatment response.
  • Pyruvate Kinase M2 (PKM2) is implicated in cancer cell metabolism and can act as a transcription factor.

Purpose of the Study:

  • To investigate the efficacy of mTOR inhibitors in CRPC cells under hypoxic conditions.
  • To explore the role of PKM2 in mediating resistance to mTOR inhibitors in CRPC.
  • To evaluate PKM2 as a potential therapeutic target in CRPC.

Main Methods:

  • Utilized C4-2AT6, a CRPC cell line, under normoxic and hypoxic (5%) conditions.
  • Administered mTOR inhibitor (RAD001) and assessed protein expression via Western blot.
  • Investigated the effect of PKM2 inhibition using si-PKM2 and analyzed clinical samples for PKM2 expression correlation.

Main Results:

  • Hypoxia significantly upregulated pAkt, pS6, HIF-1a, and PKM2 in C4-2AT6 cells, enhancing PI3K/Akt/mTOR pathway activity.
  • CRPC cells treated with mTOR inhibitor showed reduced sensitivity under hypoxia compared to normoxia.
  • Overexpression of PKM2 conferred resistance to mTOR inhibition, while PKM2 inhibition sensitized cells to the mTOR inhibitor and reduced cell viability under hypoxia.
  • High PKM2 expression in clinical samples correlated with higher Gleason scores and poorer PSA-free survival.

Conclusions:

  • Upregulation of PKM2 is a mechanism contributing to mTOR inhibitor resistance in CRPC under hypoxic conditions.
  • Targeting PKM2 presents a promising therapeutic strategy to overcome resistance and improve treatment efficacy in CRPC.
Keywords:
C4-2AT6CRPCPI3K-Akt-mTOR signaling pathwaysPKM2hypoxias

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