The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?

Abstract

Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapyinduced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.

Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition

“…The cellular localization could augment their respective functions and contribute to establishment of secretory phenotypes (31). On the other hands, another study reported that autophagy and senescence responses may occur independently without inexorable link, because senescence can develop when autophagy is abrogated (32). In principle, combining radiation with inhibition of the mTOR pathway might induce a distinctive autophagy type, resulting in autophagic cell death.…”

Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells

“…35 However, inhibition of autophagy only delays, but does not fully abrogate the senescence phenotypes. 36,37 The finding suggests that autophagy plays an accelerating role during cellular senescence. Generally, common stimuli can simultaneously induce apoptosis and autophagy in a mutually exclusive manner, which may be a result of variable thresholds for both processes or from a different cellular decision between the 2 responses, thereby linking their mutual inhibition.…”

Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

“…11 Some studies demonstrate that autophagy is positively correlated with senescence. 12,13 Conversely, increasing evidence reveals the negative correlation between autophagy and senescence. For example, Kang et al reported that autophagy impairment can induce premature senescence in primary human fibroblasts, 14 and Harrison et al verified that rapamycin, an MTOR inhibitor and an autophagy activator, can extend the life span of mice and be a potential anti-aging drug.…”