Abstract 4839: Mechanistic regulation of autophagy in the prostate cancer-bone marrow stromal microenvironment

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Abstract Autophagy is the process of intracellular digestion to reallocate nutrients and clear cells of damaged proteins and organelles. Normally, autophagy maintains cellular homeostasis and enables cell survival in unfavorable growth conditions. Alternatively, sustained autophagy can result in autophagic death of genotoxic cells. Thus, autophagy serves as a rheostat between cell survival and cell death to maintain homeostasis in the whole organism. In the context of metastatic disease, invading cells hijack autophagic processes to survive in the host environment and/or induce host cell autophagic death to enable colonization. As the most fatal characteristic of cancer is metastasis, we sought to understand how autophagy is regulated in normal and tumor cells in the metastatic niche. Building on previous work which shows that cross-talk between metastatic prostate cancer (PCa) cells and bone marrow stromal cells alters gene expression, signaling cascades, and cell proliferation and differentiation in both cell types, we hypothesize that altered autophagy also contributes to tumorigenicity in the PCa-bone marrow stromal microenvironment. Thus we have set out to determine 1) if the PCa-bone marrow stromal microenvironment alters autophagy, 2) the mechanistic regulation of autophagy in microenvironment, and 3) if autophagy can be exploited to identify markers or inhibit metastatic PCa tumorigenicity in vivo. We are using cell and molecular biology techniques to investigate autophagic signaling in co-cultures, including acridine orange to stain for acidic vesicular organelles (AVOs) and western blot analysis of the autophagosome membrane protein, microtubule-associated protein 1 light chain 3 (LC3). Our preliminary results show that in the presence of PCa cell (C4-2B)-conditioned media, bone marrow stromal cells show a marked decrease in AVOs concomitant with a significant increase in the membrane-bound form of LC3, suggesting bone marrow stromal cells can mount an autophagic defense. While free LC3 is upregulated in PCa cells exposed to bone marrow stromal cell-conditioned media, we did not observe a change in AVO accumulation or an increase in membrane-bound LC3, potentially because these end stage bone-derived PCa cells cannot solicit an effective autophagic response. Based on these and previous data from our lab, we believe events occur in the bone marrow stromal microenvironment that elicit an early defense against prostate cancer cells but eventually enable surviving PCa and tumor stromal cells to adapt and form bony tumors. Our broad goal is that the elucidation of the mechanistic regulation of autophagy in the prostate cancer-bone marrow stromal microenvironment will aide in the rational design of therapies to target bone metastatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4839.