Abstract LB-253: Tumor cells can evade survival dependence on autophagy through long term adaptation
Authors: Xiao-Ming Yin, Wen-Xing Ding, Hong-Min Ni, Xiaoyun Chen
Journal: Cancer Research (2011)

Abstract Because of their nature, tumor cells depend on multiple mechanisms for survival in suboptimal conditions. Macroautophagy, or autophagy, is an evolutionarily conserved intracellular degradation process, and it can help to protect tumor cells against nutrient deficiency, hypoxia or chemotherapeutics. To study and to compare the dependence of tumors cells vs normal cells on autophagy, we suppressed autophagy in HCT116 colon cancer cells and DU145 prostate cancer cells and found that they were much more dependent on this function to survive than normal cells when exposed to starvation or proteasome inhibitors. Suppression of autophagy in normal non-transformed cells did not significantly alter death susceptibility to the same drug. A direct comparison between two immortalized isogenic ovarian cell lines, one transformed with Ras and the other not, found that only the transformed line become more susceptible to the suppression of autophagy in the presence of a proteasome inhibitor. The transformed line also responded more strongly to general autophagy stimulation. These studies thus indicate that autophagy is a much more crucial function for transformed cells to survive, which has developed the addiction on this function. However, further analysis indicated that this dependence was not absolute, and tumor cells can adapt to the condition of minimal autophagy function. The susceptibility of tumor cells with constitutively defective autophagy to cell death was thus investigated. Transformation of wild type and Atg5-deficient murine embryonic fibroblasts (MEFs) with activated Ras did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumors. Thus the adaptation of Atg5-deficient MEFs renders them independent of autophagy for survival even in transformed status. Consistently, in an autophagy-intact glioma cell line, increased sensitivity to proteasome inhibition was induced by an acute knockdown of Beclin 1 expression with a siRNA, but not by a constitutive knockdown selected over a long period. The latter process likely had rendered the Beclin-1low cells adapted to survival independent of the function of autophagy. Taken together, we conclude that autophagy is more important to survive for tumor cells than normal cells. However, tumor cells can adapt to autophagy-deficient conditions, in which their response to chemotherapy is no longer affected by autophagy. While suppression of autophagy during cancer therapy may overcome the resistance of certain autophagy-intact tumors to the therapy, our finding now indicate that resistance to autophagy suppression/deficiency can occur in certain tumors, particularly in those tumors that arise because of the loss of autophagy capability at the very beginning. The long-term adaptation of these tumors renders them independent of autophagy for survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-253. doi:10.1158/1538-7445.AM2011-LB-253