Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of Adriamycin or Camptothecin results in both autophagy and senescence. In order to determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ATM, 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 appears to reflect their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further interrogated through pharmacologic inhibition of autophagy with chloroquine and 3-MA and genetic ablation of the autophagy-related genes ATG-5 and ATG-7. 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 appears to accelerate the development of the senescent phenotype; however, these responses are not inexorably linked or interdependent, as senescence can occur even when autophagy is abrogated.
- Received July 13, 2012.
- Revision received August 24, 2012.
- Accepted August 24, 2012.
- The American Society for Pharmacology and Experimental Therapeutics