Cyclosporin A (CsA) has antitumor effects on various cancers including prostate cancer.
However, its antitumor mechanism is poorly understood. In this study, we showed that AMP-activated protein kinase (AMPK) mediates the antitumor effect of CsA on prostate cancer cells. CsA attenuated cell growth by inducing a G1 arrest through the inhibition of mTOR complex 1 (mTORC1) signaling. In this context, Akt was paradoxically activated downstream of the EGF receptor (EGFR)-mediated increase in phosphatidylinositol 3,4,5-trisphosphate (PIP3) production. However, CsA also caused a Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)-dependent activation of AMPK, which inhibits mTORC1 signaling; this led to ineffective Akt signaling. An EGFR or Akt inhibitor increased the growth suppressive activity of CsA, whereas the combination of an AMPK inhibitor and CsA markedly rescued cells from the G1 arrest and increased cell growth. These results provide novel insights into the molecular mechanisms of CsA on cancer signaling pathways.
Written by:
Lee CR, Chun JN, Kim SY, Park S, Kim SH, Park EJ, Kim IS, Cho NH, Kim IG, So I, Kim TW, Jeon JH. Are you the author?
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Reference: Biochem Pharmacol. 2012 Aug 15;84(4):425-31.
doi: 10.1016/j.bcp.2012.05.009
PubMed Abstract
PMID: 22634404
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