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

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

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18 Citations (Scopus)

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 (PIP 3) production. However, CsA also caused a Ca 2+/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.

Original languageEnglish
Pages (from-to)425-431
Number of pages7
JournalBiochemical Pharmacology
Volume84
Issue number4
DOIs
Publication statusPublished - 2012 Aug 15

Keywords

  • AMPK
  • Akt
  • Cyclosporin A
  • Prostate cancer
  • mTOR

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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  • Cite this

    Lee, C. R., Chun, J. N., Kim, S. Y., Park, S., Kim, S. H., Park, E. J., Kim, I. S., Cho, N. H., Kim, I. G., So, I., Kim, T. W., & Jeon, J. H. (2012). Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling. Biochemical Pharmacology, 84(4), 425-431. https://doi.org/10.1016/j.bcp.2012.05.009