Abstract 2663: Dual cytoprotective and cytotoxic functions of autophagy in the response ofbreast tumor cells to radiation and in radiosensitization by vitamin D3

Abstract

Listen

Translate article

Abstract Introduction: While chemotherapy and radiation treatment may be initially effective at suppressing breast cancer growth, disease recurrence and tumor metastasis are major clinical problems. A number of strategies have been developed in an attempt to enhance the response to radiation and prevent tumor cell recovery by interfering with cytoprotective signaling. Autophagy, a cellular process in which the degradation of subcellular organelles generates energy and metabolic precursors, may be cytoprotective or cytotoxic, depending on the cells and the nature of the stressful challenge. Our studies were designed to evaluate the involvement of autophagy in radiosensitization by the hormonally active form of vitamin D3, 1,25D3. Additionally, studies were designed to test the premise that interference with autophagy would influence sensitivity to treatment with 1,25D3 + radiation. Results: Our studies demonstrate radiosensitization of breast tumor cells by vitamin D (1,25D3) through the promotion of autophagy as well as a concurrent cytoprotective function of autophagy in irradiated cells. 1,25D3 promoted autophagy (as well as autophagic flux) in irradiated MCF7 cells and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in p53 mutant Hs578t breast tumor cells as well as MCF7 cells that overexpress Her-2/neu. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by either a pharmacological or genetic block to autophagy due to a shift in the mode of cell death to apoptosis. In contrast to autophagy mediating the cytotoxic impact of the 1,25D3 and radiation combination treatment, radiation alone promoted a low level of autophagy that was cytoprotective. Specifically, pharmacological or genetic interference with autophagy induced by radiation resulted in cell killing (primarily by apoptosis). These studies demonstrate that in the same experimental system, autophagy can function both as a mechanism for evading cell killing by radiation and as a pathway for mediating the killing of breast tumor cells by radiation. Conclusions: Both the suppression of cytoprotective autophagy and the promotion of cytotoxic autophagy represent potential strategies for radiation sensitization in breast cancer. Supported, in part, by American Institute for Cancer Research Grant # 06A058-REV and by DOD predoctoral training grant W81XWH-09-1-0020. 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 2663. doi:10.1158/1538-7445.AM2011-2663