Autophagy suppresses tumor progression by limiting chromosomal instability.

By Robin Mathew, S. Kongara, Brian Beaudoin, Cristina M. Karp, Kevin Bray, K. Degenhardt, Guanghua Chen, Shengkan Jin, E. White. Genes & Development, 2007

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Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.

Subfields: Cancer Research, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a5ade47e2945d812832efebadf110a8e205802b7

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Citations in the corpus

Autophagy: process and function. (2007, background): “In addition to nutrient limitation, it has been suggested that autophagy might be responsive to hypoxia: Autophagy is induced in a mouse cerebral ischemia-hypoxia model (Adhami et al. 2006) and in ischemic myocardium (Yan et al. 2005; Matsui et al. 2007).”
Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. (2007, background): “These findings are similar to what was reported when apoptosis was disabled by bax and bak deficiency in immortalized baby mouse kidney (iBMK) cells (Degenhardt et al. 2006) or Bcl-2 expression in iBMK cells (Degenhardt et al. 2006; Mathew et al. 2007).”
The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. (2010, background): “During carcinogenesis autophagy suppresses tumor progression through stabilization of the genome (58, 59), perhaps related to the inability to clear the cell of damaged organelles or toxic protein aggregates.”
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity (2010, background): “Accumulated evidence has shown that the autophagic process is related to cell cycle regulation, starvation adaptation, ageing, and cancer developmen”
Recent insights into the function of autophagy in cancer (2016, background): “These events are a source of genomic instability and oncogenic signal transduction that promote cancer initiation (Karantza-Wadsworth et al. 2007; Mathew et al. 2007, 2009) commonly found in states of chronic inflammation induced by a broad array of stimuli.”
Principles and Current Strategies for Targeting Autophagy for Cancer Treatment (2011, background): “damaging ROS production, contributing to mutations that can initiate cancer and promote tumor progression (40).”
Autophagy and autophagy-related proteins in cancer (2020, background): “and an elevated mutation rate has been found in the autophagy-deficient cancer cells [237].”
The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance (2011, background): “In mouse models, autophagy has also been shown to suppress tumors by preventing the accumulation of DNA damage (Mathew et al., 2007) and p62 aggregates (Komatsu et al., 2007; Mathew et al., 2009).”