Abstract
For many cancer patients, cytotoxic chemotherapy is the primary treatment option. While the goal of these treatments is to induce tumor cell apoptosis, treatments too often fail as tumor cells possess the dynamic ability to subvert cell death and become chemoresistant. We are interested in determining the mechanisms by which tumors develop chemoresistance, with the goal of identifying potential therapeutic targets/pathways to increase the efficacy of chemotherapy. One context in which tumor cells are though to gain.14-3-3ζ is a small acidic protein that binds to phospho-serine proteins. 14-3-3ζ binding can have wide ranging effects, from the activation of enzyme function, to the orchestration of protein-protein interactions. 14-3-3ζ is highly expressed in many cancer types, and high levels of expression have been shown to correlate with the aggressiveness of tumors and lower rates of patient survival (1). However, the mechanisms by which 14-3-3ζ may promote tumor growth/tumor cell survival have yet to be determined. In this study we show that siRNA-mediated depletion of 14-3-3ζ potently sensitizes breast tumor cells to apoptosis induced by metabolic stress (e.g., hypoxia and glucose withdrawal_stresses commonly found within solid tumors) and chemotherapy. Moreover, gel filtration data suggest that metabolic cell stress induces a shift in 14-3-3ζ from high to lower molecular weight protein complexes. Drawing from these data, we performed a proteomics experiment to characterize 14-3-3ζ interactors under these conditions. We found that 14-3-3ζ associates with numerous pro-glycolysis- and cell growth-regulating enzymes (several of which are novel 14-3-3ζ interactors), and under conditions of metabolic stress, many of these interactions are diminished or lost. We are currently examining the functional consequences of these dynamic 14-3-3z interactions with respect to tumor cell survival. Together, our data suggest that 14-3-3ζ may play an apical role in regulating the metabolic response to stress, and provide insight into the mechanism by which 14-3-3ζ promotes tumor growth and survival.
Citation Format: Vajira K. Weerasekara, Jeffrey B. Mortenson, Joshua L. Andersen. 14-3-3z-mediated suppression of tumor cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 851. doi:10.1158/1538-7445.AM2013-851