Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells

The Journal of Clinical Investigation
Makoto SumitomoMasamichi Hayakawa

Abstract

We studied the role of protein kinase C isoform PKCdelta in ceramide (Cer) formation, as well as in the mitochondrial apoptosis pathway induced by anticancer drugs in prostate cancer (PC) cells. Etoposide and paclitaxel induced Cer formation and apoptosis in PKCdelta-positive LNCaP and DU145 cells but not in PKCdelta-negative LN-TPA or PC-3 cells. In contrast, these drugs induced mitotic cell cycle arrest in all PC cell lines. Treatment with Rottlerin, a specific PKCdelta inhibitor, significantly inhibited drug-induced Cer formation and apoptosis in LNCaP cells, as did overexpression of dominant negative-type PKCdelta. Overexpression of wild-type PKCdelta had an opposite effect in PC-3 cells. Notably, etoposide induced biphasic Cer formation in LNCaP cells. The early and transient Cer increase resulted from de novo Cer synthesis, while the late and sustained Cer accumulation was derived from sphingomyelin hydrolysis by neutral sphingomyelinase (nSMase). Cer, in turn, induced mitochondrial translocation of PKCdelta and stimulated the activity of this kinase, promoting cytochrome c release and caspase-9 activation. Furthermore, the specific caspase-9 inhibitor LEHD-fmk significantly inhibited etoposide-induced nSMase activation, ...Continue Reading

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Citations

Aug 25, 2012·Archivum Immunologiae Et Therapiae Experimentalis·Meng ZhaoGuo-Qiang Chen
Feb 13, 2007·Apoptosis : an International Journal on Programmed Cell Death·Andrea Rasola, Paolo Bernardi
May 27, 2005·Cancer Letters·Barbara MarengoCinzia Domenicotti
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Apr 2, 2011·The Journal of Biological Chemistry·HongBin WangMarcelo G Kazanietz
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Feb 24, 2015·Apoptosis : an International Journal on Programmed Cell Death·Sehamuddin GaladariFaisal Thayyullathil

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Methods Mentioned

BETA
FCS
flow
ELISA
transfection
SMase

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