Downregulated adaptor protein p66Shc mitigates autophagy process by low nutrient and enhances apoptotic resistance in human lung adenocarcinoma A549 cells

Authors

  • Zhichao Zheng,

    1. Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, China
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  • Jie Yang,

    1. Department of Biochemistry and Molecular Biology, Tianjin Medical University, China
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  • Dan Zhao,

    1. Department of Biochemistry and Molecular Biology, Tianjin Medical University, China
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  • Dan Gao,

    1. Department of Biochemistry and Molecular Biology, Tianjin Medical University, China
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  • Xiaojie Yan,

    1. Department of Biochemistry and Molecular Biology, Tianjin Medical University, China
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  • Zhi Yao,

    1. Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, China
    2. 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, China
    3. Key Laboratory of Immune Microenviroment and Disease of the Ministry of Education, Tianjin Medical University, China
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  • Zhe Liu,

    Corresponding author
    1. Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, China
    2. Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, China
    3. Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, China
    4. 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, China
    5. Key Laboratory of Immune Microenviroment and Disease of the Ministry of Education, Tianjin Medical University, China
    • Correspondence

      Z. Liu, Tianjin Key Laboratory of Medical Epigenetics, Depatrment of Immunology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenviroment and Disease of the Ministry of Education, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China

      Fax: +86 22 8333 6533

      Tel.: +86 22 8333 6833

      E-mail: zheliu@tmu.edu.cn

      Z. Ma, Department of Biochemistry and Molecular Biology, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China

      Fax: +86 22 8333 6533

      Tel.: +86 22 8333 6833

      E-mail: zhyma@tmu.edu.cn

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  • Zhenyi Ma

    Corresponding author
    1. Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, China
    2. Department of Biochemistry and Molecular Biology, Tianjin Medical University, China
    • Correspondence

      Z. Liu, Tianjin Key Laboratory of Medical Epigenetics, Depatrment of Immunology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenviroment and Disease of the Ministry of Education, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China

      Fax: +86 22 8333 6533

      Tel.: +86 22 8333 6833

      E-mail: zheliu@tmu.edu.cn

      Z. Ma, Department of Biochemistry and Molecular Biology, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China

      Fax: +86 22 8333 6533

      Tel.: +86 22 8333 6833

      E-mail: zhyma@tmu.edu.cn

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  • Zhichao Zheng and Jie Yang contributed equally to this article

Abstract

Macroautophagy or autophagy is a lysosome-dependent process in which enzymatic degradation and recycling of cytosolic components occur in stressful contexts. The mechanisms underlying the signaling from starvation to the regulation of autophagy are not fully understood. We previously showed that the Src family member p66Shc (focal adhesion-associated 66 kDa isoform of the Src homology and collagen) promotes anoikis and suppresses tumor metastasis via k-Ras-dependent control of proliferation and survival. However, the role of p66Shc in low-nutrient-induced autophagy-related pathways remains elusive. In this work, human lung adenocarcinoma A549 cells were used to further investigate the biological effects of p66Shc on autophagy and apoptotic resistance. Here, we show that deficiency of p66Shc mitigates the low-nutrient-induced autophagy process in the levels of microtubule-associated protein 1A light chain protein 3B (LC3B) conversion, in the number of autophagic vacuoles and in p62/sequestosome 1 protein degradation. However, autophagy-related protein Beclin 1 was not significantly changed during low-nutrient treatment. Furthermore, we found that prolonged phosphorylation of extracellular signaling-regulated kinase (Erk)1/2, but not phosphorylation of Akt is significantly sustained when p66Shc expression is inhibited by shRNA. In addition, cleavage of caspase 7 and poly(ADP-ribose) polymerase, but not caspase 6 and 9 are retarded with this effect compared to the shRNA control cells. Together, these findings suggest the possibility that p66Shc plays a pivotal role in coordinately regulating autophagy process and apoptotic resistance in A549 cells under nutrient-limited conditions.

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