Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling.
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.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Chae Ryun
CR
Lee
Jung Nyeo
JN
Chun
Sang-Yeob
SY
Kim
Soonbum
S
Park
Su-Hwa
SH
Kim
Eun-Jung
EJ
Park
In-San
IS
Kim
Nam-Hyuk
NH
Cho
In-Gyu
IG
Kim
Insuk
I
So
Tae Woo
TW
Kim
Ju-Hong
JH
Jeon
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010716:Phosphatidylinositols / Q000378:metabolism; D011471:Prostatic Neoplasms; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D010716:Phosphatidylinositols; D011506:Proteins; C118303:phosphoinositide-3,4,5-triphosphate; D016572:Cyclosporine; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases