title: TGF-β1/PTEN/PI3K signaling plays a critical role in the anti-proliferation effect of tetrandrine in human colon cancer cells.
abstract: The diagnosis and treatment for colon cancer have been greatly developed, but the prognosis remains unsatisfactory. There is still a great clinical need to explore new efficacious drugs for colon cancer treatment. Tetrandrine (Tet) is a bis-benzylisoquinoline alkaloid. It has been shown that Tet may be a potential candidate for cancer treatment, but the explicit mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Tet in human colon cancer cells and dissected the possible mechanism. With cell viability assay and flow cytometry analysis, we confirmed that Tet can effectively inhibit the proliferation and induce apoptosis in HCT116 cells. Mechanically, we found that Tet greatly increases the mRNA and protein level of TGF-β1 in HCT116 cells. Exogenous TGF-β1 enhances the anti-proliferation and apoptosis inducing effect of Tet in HCT116 cells, which has been partly reversed by TGF-β1 inhibitor. Tet decreases the phosphorylation of Akt1/2/3 in HCT116 cells. This effect can be enhanced by exogenous TGF-β1, but partly reversed by TGF-β1 inhibitor. Tet exhibits no effect on total level of PTEN, but decreases the phosphorylation of PTEN; exogenous TGF-β1 enhances the effect of Tet on decreasing the phosphorylation of PTEN, which was partly reversed by TGF-β1 inhibitor. Our findings suggested that Tet may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating TGF-β1 to decrease the phosphorylation of PTEN.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Qian-Zhao
authors.initials: QZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Wen-Yan
authors.initials: WY
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Rong-Xing
authors.initials: RX
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Lin-Yun
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: Hu
authors.affiliation: Chongqing Key Laboratory for Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory for Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D045325:HCT116 Cells; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053773:Transforming Growth Factor beta1; C009438:tetrandrine; C494929:PTEN protein, human