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Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells.
Drug Des Devel Ther. 2015; 9:1511-54.DD

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+Show Affiliations

Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia, People's Republic of China.Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.Department of Psychiatry and Behavioral Neurosciences, Silver Child Development Center, Rashid Laboratory for Developmental Neurobiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25834399

Citation

Zhou, Zhi-Wei, et al. "Induction of Apoptosis and Autophagy Via Sirtuin1- and PI3K/Akt/mTOR-mediated Pathways By Plumbagin in Human Prostate Cancer Cells." Drug Design, Development and Therapy, vol. 9, 2015, pp. 1511-54.
Zhou ZW, Li XX, He ZX, et al. Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Des Devel Ther. 2015;9:1511-54.
Zhou, Z. W., Li, X. X., He, Z. X., Pan, S. T., Yang, Y., Zhang, X., Chow, K., Yang, T., Qiu, J. X., Zhou, Q., Tan, J., Wang, D., & Zhou, S. F. (2015). Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Design, Development and Therapy, 9, 1511-54. https://doi.org/10.2147/DDDT.S75976
Zhou ZW, et al. Induction of Apoptosis and Autophagy Via Sirtuin1- and PI3K/Akt/mTOR-mediated Pathways By Plumbagin in Human Prostate Cancer Cells. Drug Des Devel Ther. 2015;9:1511-54. PubMed PMID: 25834399.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. AU - Zhou,Zhi-Wei, AU - Li,Xing-Xiao, AU - He,Zhi-Xu, AU - Pan,Shu-Ting, AU - Yang,Yinxue, AU - Zhang,Xueji, AU - Chow,Kevin, AU - Yang,Tianxin, AU - Qiu,Jia-Xuan, AU - Zhou,Qingyu, AU - Tan,Jun, AU - Wang,Dong, AU - Zhou,Shu-Feng, Y1 - 2015/03/12/ PY - 2015/4/3/entrez PY - 2015/4/4/pubmed PY - 2016/5/18/medline KW - AMPK KW - DU145 KW - PC-3 KW - ROS KW - visfatin SP - 1511 EP - 54 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - 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. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/25834399/Induction_of_apoptosis_and_autophagy_via_sirtuin1__and_PI3K/Akt/mTOR_mediated_pathways_by_plumbagin_in_human_prostate_cancer_cells_ L2 - https://dx.doi.org/10.2147/DDDT.S75976 DB - PRIME DP - Unbound Medicine ER -