p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation

Abstract

The p53 tumor suppressor is mutated in a high percentage of human tumors. However, many other tumors retain wild-type (wt) p53 expression, raising the intriguing possibility that they actually benefit from it. Recent studies imply a role for p53 in regulation of autophagy, a catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles, particularly under conditions of nutrient deprivation. Here, we show that, in many cell types, p53 confers increased survival in the face of chronic starvation. We implicate regulation of autophagy in this effect. In HCT116 human colorectal cancer cells exposed to prolonged nutrient deprivation, the endogenous wt p53 posttranscriptionally down-regulates LC3, a pivotal component of the autophagic machinery. This enables reduced, yet sustainable autophagic flux. Loss of p53 impairs autophagic flux and causes excessive LC3 accumulation upon starvation, culminating in apoptosis. Thus, p53 increases cell fitness by maintaining better autophagic homeostasis, adjusting the rate of autophagy to changing circumstances. We propose that some cancer cells retain wt p53 to benefit from the resultant increased fitness under limited nutrient supply.apoptosis | posttranscriptional regulation

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…This may suggest a regulatory role for cytoplasmic p53 on autophagy pathway for maintaining cellular homeostasis to increase cell survival in face of nutrient deprivation. p53 degradation in response to chronic starvation and endoplasmic reticulum stress stimulates autophagy pathways, resulting in high levels of intracellular ATP associated with better cell viability (McCormick et al 2012;Scherz-Shouval et al 2010). For instance, induction of autophagy in p53-deficient colorectal cancer cells exposed to prolonged nutrient deprivation maintains high ATP levels and improves the survival rate of these cells (Scherz-Shouval et al 2010).…”

p53-dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene

“…Interestingly, PanK1β mRNA level was induced induces autophagy in the face of prolonged starvation to generate sufficient energy for survival through regulation on LC3. 15 Together, this evidence suggests that p53, besides being a tumor suppressor, may also play a prosurvival role of maintaining metabolic homeostasis under energy crisis.…”

Autophagic activity dictates the cellular response to oncogenic RAS

“…A recent study also showed that p53 is able to regulate autophagic activity by inducing the expression of LC3 (13). However, it remains unknown whether the ability of p53 to induce autophagy is required to mediate oncogenic RAS-induced senescence.…”