title: Detachment-Based Equilibrium of Anoikic Cell Death and Autophagic Cell Survival Through Adaptor Protein p66(Shc).
abstract: Anoikis (detachment-induced cell death) confers a tumor-suppressive function in metastatic cancer cells. Autophagy, a conserved self-degradative process, enhances the anoikis resistance of detached cancer cells by maintaining cellular homeostasis. However, the mechanism of regulating cell fate-decision by balancing anoikis and autophagy has been poorly understood. Our previous studies have shown that the adaptor protein p66(Shc) mediates anoikis through RhoA activation and inhibits tumor metastasis in vivo. We also found that p66(Shc) depletion mitigates nutrient-deprivation-induced autophagy. These findings suggest p66(Shc) may coordinately regulate these two processes. To verify this hypothesis, we investigated the effect of p66(Shc) on the cell death of detached lung cancer cells, and measured autophagy markers and autophagic flux. Results showed that p66(Shc) depletion significantly inhibited anoikis, and reduced the formation of LC3B-II and the degradation of Sequestosome 1 (SQSTM1, p62) in detachment-induced cells. Using monodansylcadaverine (MDC)-LysoTracker double staining and monomeric Cherry (mCherry)-GFP-LC3 assay, we found that the autophagic flux was also mitigated by p66(Shc) depletion. In addition, p66(Shc) knockdown increased the formation of full-length X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), which enhances anoikis sensitivity. In conclusion, p66(Shc) plays an essential role in detachment-based equilibrium of anoikic cell death and autophagic cell survival.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.|Department of Cardiovascular Institute, Tianjin Chest Hospital, Tianjin, 300222, China.
authors.forename: Zeyuan
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Key Laboratory of Systems Bioengineering (Ministry of Education), Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Ma
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing; D023102:Anoikis; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D002470:Cell Survival; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D047908:Intracellular Signaling Peptides and Proteins; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C528024:SHC1 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C417551:XAF1 protein, human
keywords: Shc; anoikis; autophagy; detachment; lung cancer