Cyclosporin A suppresses prostate cancer cell growth through CaMKK¦Â/AMPK-mediated inhibition of mTORC1 signaling

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• 作者：Chae Ryun Lee ; Jung Nyeo Chun ; Sang-Yeob Kim ; Soonbum Park ; Su-Hwa Kim ; Eun-Jung Park ; In-San Kim ; Nam-Hyuk Cho ; In-Gyu Kim ; Insuk So ; Tae Woo Kim ; Ju-Hong Jeon
• 关键词：Cyclosporin A ; AMPK ; Akt ; mTOR ; Prostate cancer
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 出版时间：15 August, 2012
• 年：2012
• 卷：84
• 期：4
• 页码：425-431
• 全文大小：1145 K

文摘

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 ¦Â (CaMKK¦Â)-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.