title: ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells.
abstract: Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.|Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yaochen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.|Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Jin
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193, China.
authors.forename: Guanwei
authors.initials: G
authors.lastname: Fan
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.|Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*
chemical_list: D014227:Triazines; C510150:ZSTK474; D019938:Cyclin D1; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: G1 arrest; MCF-7; PI3K inhibitor; ZSTK474; autophagy