Dual action of NSC606985 on cell growth and apoptosis mediated through PKCδ in prostatic cancer cells

Wang,Xin; Tan,Chen; Wang,Guo; Cai,Jing-Jing; Wang,Li-Ping; Imperato-McGinley,Julianne; Zhu,Yuan-Shan

doi:10.3892/ijo.2017.4138

Dual action of NSC606985 on cell growth and apoptosis mediated through PKCδ in prostatic cancer cells

Authors:
- Xin Wang
- Chen Tan
- Guo Wang
- Jing-Jing Cai
- Li-Ping Wang
- Julianne Imperato-McGinley
- Yuan-Shan Zhu
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Affiliations: Department of Medicine/Endocrinology, Weill Cornell Medicine, New York, NY 10065, USA
Published online on: September 27, 2017 https://doi.org/10.3892/ijo.2017.4138
Pages: 1601-1610

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Abstract

Chemotherapy is a vital therapeutic strategy for castration-resistant prostate cancer (CRPC). We have previously shown that NSC606985 (NSC), a camptothecin (CPT) analog, induced cell apoptosis via interacting with topoisomerase I (Topo I) in prostate cancer cells. In the present study, the effect and mechanism of CPT analogs in LAPC4 cells were investigated. LAPC-4 cells were treated with NSC, CPT, and topotecan. Cell proliferation, apoptosis, and protein kinase Cδ (PKCδ) subcellular activation were measured at different doses and time-points, with or without PKCδ inhibition or knockdown of PKCδ expression. NSC at doses ranging from 10 to 100 nM induced a dose-dependent increase in viable cell number and DNA biosynthesis with mild cell apoptosis, whereas, at doses ranging from 500 nM to 5 mM, NSC produced a dose-dependent decrease in cell proliferation and DNA biosynthesis with a significant induction of cell apoptosis. Both NSC-induced cell proliferation and apoptosis were blocked by knockdown of PKCδ with a specific RNAi, or by the co-administration of rottlerin, a PKCδ inhibitor. Moreover, NSC produced a dose-dependent subcellular activation of PKCδ. The dose-dependent dual action of NSC is mediated at least in part through the differential subcellular activation of PKCδ in LAPC4 cells. The demonstration of a differential cell response to camptothecin analogs would facilitate the identification of biomarker(s) to CPT sensitivity and promote the personalization of CPT chemotherapy in CRPC.

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