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
2009
Key concepts
- signal transduction
- SQSTM1
- mitochondria
- gene expression
- lysosomes
- Natural Killer
- endoplasmic reticulum
- Gene Set Enrichment Analysis
- N-acetyl cysteine
- tumor cell
- tumorigenesis
- tissue microarray
- protein aggregate
- reactive oxygen
- oncogenesis
- oxidative stress
- hepatocellular carcinoma
- tumor suppression
- Electron Microscopy
- reactive oxygen species
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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