Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells.

Abstract

Plumbagin (PLB) has been shown to have anticancer activities in animal models, but the role of PLB in prostate cancer treatment is unclear. This study aimed to investigate the effects of PLB on apoptosis and autophagy and the underlying mechanisms in human prostate cancer cell lines PC-3 and DU145. Our study has shown that PLB had potent pro-apoptotic and pro-autophagic effects on PC-3 and DU145 cells. PLB induced mitochondria-mediated apoptosis and autophagy in concentration- and time-dependent manners in both PC-3 and DU145 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways and activation of 5'-AMP-dependent kinase (AMPK) as indicated by their altered phosphorylation, contributing to the pro-autophagic activity of PLB. Modulation of autophagy altered basal and PLB-induced apoptosis in both cell lines. Furthermore, PLB downregulated sirtuin 1 (Sirt1), and inhibition of Sirt1 enhanced autophagy, whereas the induction of Sirt1 abolished PLB-induced autophagy in PC-3 and DU145 cells. In addition, PLB downregulated pre-B cell colony-enhancing factor/visfatin, and the inhibition of pre-B cell colony-enhancing factor/visfatin significantly enhanced basal and PLB-induced apoptosis and autophagy in both cell lines. Moreover, reduction of intracellular reactive oxygen species (ROS) level attenuated the apoptosis- and autophagy-inducing effects of PLB on both PC-3 and DU145 cells. These findings indicate that PLB promotes apoptosis and autophagy in prostate cancer cells via Sirt1- and PI3K/Akt/mTOR-mediated pathways with contribution from AMPK-, p38 MAPK-, visfatin-, and ROS-associated pathways.

• Authors: Zhi-Wei Zhou, Xing-Xiao Li, Zhi-Xu He, Shu-Ting Pan, Yinxue Yang, Xueji Zhang, Kevin Chow, Tianxin Yang, Jia-Xuan Qiu, Qingyu Zhou, Jun Tan, Dong Wang, Shu-Feng Zhou
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 9 Pg. 1511-54 ( 2015) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 25834399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Naphthoquinones
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirtuin 1
• plumbagin

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Male
• Mitochondria (drug effects, metabolism)
• Molecular Structure
• Naphthoquinones (chemistry, pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1 (metabolism)
• Structure-Activity Relationship
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Cells, Cultured