title: Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells.
abstract: Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5'-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of PI3K/protein kinase B/mammalian target of rapamycin and p38 MAPK mediated pathways.
authors: Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors: Feng
authors: F
authors: Wang
authors: Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors: Qi
authors: Q
authors: Wang
authors: Department of Pharmaceutical Science, 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, Guiyang Medical University, Guiyang, People's Republic of China.
authors: Zhi-Wei
authors: ZW
authors: Zhou
authors: Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors: Song-Ning
authors: SN
authors: Yu
authors: Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
authors: Shu-Ting
authors: ST
authors: Pan
authors: Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's Republic of China.
authors: Zhi-Xu
authors: ZX
authors: He
authors: Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.
authors: Xueji
authors: X
authors: Zhang
authors: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors: Dong
authors: D
authors: Wang
authors: Department of Colorectal Surgery, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors: Yin-Xue
authors: YX
authors: Yang
authors: Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors: Tianxing
authors: T
authors: Yang
authors: Key Lab of Craniocerebral Diseases of Ningxia, Ningxia Medical University, Yinchuan, People's Republic of China.
authors: Tao
authors: T
authors: Sun
authors: Department of Medicine and Department of Surgery, The University of Oklahoma Health Sciences Center, Stanton L Young Biomedical Research Center, Oklahoma City, OK, USA.
authors: Min
authors: M
authors: Li
authors: Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
authors: Jia-Xuan
authors: JX
authors: Qiu
authors: Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors: Shu-Feng
authors: SF
authors: Zhou
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D009285:Naphthoquinones; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C014758:plumbagin
keywords: EMT; Plumbagin; Sirt1; autophagy; cell cycle; pancreatic cancer
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