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Published on: June 30, 2023
Oncogene-mediated tumor transformation sensitizes cells to autophagy induction
Ricardo Gargini1, Vega García-Escudero1, Marta Izquierdo1
1Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
Abstract:
The process of tumorigenesis induces alterations in numerous cellular pathways including the main eukaryotic metabolic routes. It has been recently demonstrated that autophagy is part of the oncogene-induced senescence phenotype although its role in tumor establishment has not been completely clarified. In the present study, we showed that non‑transformed cells are sensitized to mitochondrial stress and autophagy induction when they are transformed by oncogenes such as c-Myc or Ras. We observed that overexpression of c-Myc or Ras increased AMP-activated protein kinase (AMPK) phosphorylation and the expression of p62, a known partner for degradation by autophagy. The activation of AMPK was found to favor the activation of FoxO3 which was prevented by the inhibition of AMPK. The transcriptional activation mediated by FoxO3 upregulated genes such as BNIP3 and LC3. Finally, the transformation by oncogenes such as c-Myc and Ras predisposes tumor cells to autophagy induction as a consequence of mitochondrial stress and impairs tumor growth in vitro and in vivo, which may have therapeutic implications.
Insights
Oncogene transformation sensitizes cells to mitochondrial stress and autophagy. This process, involving AMP-activated protein kinase (AMPK) and FoxO3, impairs tumor growth, suggesting potential therapeutic strategies for cancer.
Area of Science:
- Cellular Biology
- Cancer Research
- Metabolism
Background:
- Tumorigenesis involves significant alterations in cellular metabolic pathways.
- Autophagy's role in tumor establishment is not fully understood, though linked to oncogene-induced senescence.
Purpose of the Study:
- To investigate how oncogenes like c-Myc and Ras affect cellular stress responses and autophagy.
- To clarify the role of autophagy in tumor development and its potential as a therapeutic target.
Main Methods:
- Overexpression of oncogenes (c-Myc, Ras) in non-transformed cells.
- Analysis of AMP-activated protein kinase (AMPK) phosphorylation, p62 expression, and FoxO3 activation.
- Assessment of autophagy-related gene expression (BNIP3, LC3) and tumor growth in vitro and in vivo.
Main Results:
- Oncogene transformation sensitized cells to mitochondrial stress and induced autophagy.
- Overexpression of c-Myc/Ras increased AMPK phosphorylation and p62 expression.
- AMPK activation promoted FoxO3 activation, upregulating BNIP3 and LC3, ultimately impairing tumor growth.
Conclusions:
- Oncogene transformation predisposes cells to autophagy induction due to mitochondrial stress.
- This autophagy induction impairs tumor growth, indicating a potential tumor-suppressive role in this context.
- Findings suggest therapeutic strategies targeting autophagy in cancer treatment.
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