Autophagy Suppresses Tumorigenesis through Elimination of p62

We report here that metabolic stress caused autophagydefective tumor cells to preferentially accumulate p62, endoplasmic reticulum chaperones and protein disulphide isomerases, indicative of protein quality control failure

Robin Mathew; Cristina M. Karp; Brian Beaudoin; Nhan Vuong; Guanghua Chen; Hsin-Yi Chen; Kevin Bray; Anupama Reddy; Gyan Bhanot; Celine Gelinas; Robert S. DiPaola; Vassiliki Karantza-Wadsworth; Eileen White


Scholarcy highlights

  • Macroautophagy targets cellular proteins, protein aggregates and organelles for degradation in lysosomes
  • Autophagy-Defective Tumor Cells Accumulate p62 in Response to Stress To address the role of autophagy-dependant protein quality control in tumor suppression, we assessed p62 modulation during metabolic stress and recovery in autophagy-competent and -defective immortalized baby mouse kidney cells
  • Cells were engineered to express Bcl-2, as assessment of autophagy is facilitated in an apoptosis-defective background and expression of Bcl-2 is functionally equivalent to loss of Bax and Bak in the context of autophagy modulation and tumorigenesis
  • Endogenous p62 levels were low by indirect immunofluorescence in beclin1+/+ and atg5+/+ cells and slightly elevated in autophagydefective immortalized baby mouse kidney cells
  • This enhanced survival provided by N-acetyl cysteine was associated with decreased p62 accumulation during metabolic stress in the beclin1+/À and atg5À/À iBMK cells, suggesting that reactive oxygen species-mediated oxidative stress leads to protein damage and accumulation of p62
  • P62 accumulation in hepatocytes was heterogenous. beclin1+/À hepatocytes that accumulated high p62 did not display nuclear p65 whereas those with less p62 showed nuclear localization of p65. This suggests that as in the IKKb- and NEMO-deficient hepatocyes, defective autophagy and deregulation of p62 was associated with suppression of the canonical NF-kB pathway, impaired survival and Accumulation of p62 in response to metabolic stress is a striking phenotype of autophagy-defective tumors cells, suggesting defective protein quality control may contribute to tumorigenesis and that autophagy is the main mechanism by which tumor cells turnover p62
  • Defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis

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