1. Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling.
- Author
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Lee CR, Chun JN, Kim SY, Park S, Kim SH, Park EJ, Kim IS, Cho NH, Kim IG, So I, Kim TW, and Jeon JH
- Subjects
- Cell Proliferation drug effects, Enzyme Activation, ErbB Receptors metabolism, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Phosphatidylinositols metabolism, Prostatic Neoplasms, Signal Transduction, TOR Serine-Threonine Kinases, AMP-Activated Protein Kinases metabolism, Antineoplastic Agents pharmacology, Calcium-Calmodulin-Dependent Protein Kinase Kinase metabolism, Cyclosporine pharmacology, Proteins metabolism
- Abstract
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., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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