Abstract
Abstract
Our laboratory has previously described the four functional forms of autophagy, specifically cytoprotective, cytotoxic, cytostatic and nonprotective (Gewirtz DA, Cancer Research 2014). Evidence for the nonprotective form was based on studies where murine 4T1 breast tumor cells failed to be sensitized to ionizing radiation by pharmacological or genetic inhibition of autophagy (Bristol ML, JPET, 2013). To determine whether radiation induces the cytoprotective and nonprotective forms of autophagy in human tumor cells lines of different tissue origin, the influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck and non-small cell lung cancer cell lines. In order to examine the potential involvement of p53 in the protective and nonprotective forms of autophagy, the impact of autophagy inhibition on radiation sensitivity was compared in cell lines that were either wild type or mutant/null in p53. While ionizing radiation promoted autophagy in all tumor cell lines studied, autophagy inhibition resulted in radiation sensitivity only in the p53 wild type A549 and H460 NSCLC cells and the HN30 head and neck tumor cells. In contrast, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in the p53 mutant Hs578t breast tumor cells, the HN6 head and neck tumor cells, and the H358 non-small cell lung cancer cells, indicative of nonprotective autophagy. The apparent requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild-type HN30 cells did show sensitization to radiation upon autophagy inhibition HN30 cells in which p53 was knocked down were not sensitized. These observations have implications for efforts to modulate the response of malignancies to radiation (and possibly also to cancer chemotherapeutic drugs) through autophagy inhibition.
Citation Format: Shweta Chakradeo, Khushboo Sharma, Aisha Alhaddad, Duaa Bakhshwin, Ngoc Le, Hisashi Harada, W. Andrew Yeudall, Suzy Torti, Frank Torti, David Gewirtz. Induction of non-protective autophagy by radiation in tumor cells: Implications for autophagy inhibition as a therapeutic strategy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2015-998