Abstract SY36-03: Development of small-molecule inhibitors of autophagy as anticancer therapy

Abstract

Abstract Autophagy is an intracellular catabolic mechanism that sequesters selected cytoplasmic components and organelles into double-membrane vesicles, called autophagosomes; the content of autophagosomes is degraded by lysosomal hydrolases after fusing with lysosomes. Autophagy is an important homeostatic mechanism that regulates intracellular recycling and supports cellular survival under stressful conditions (Moreau et al., 2010). Activation of autophagy confers stress resistance and sustains cell survival under adverse conditions. Consistently, autophagy has been found to play an important role in promoting cancer cell survival in the tumor micro-environment in vivo and contribute to metabolic changes to promote oncogenic transformation (Lock et al., 2010). Furthermore, activation of autophagy has been implicated in mediating resistance to existing anticancer therapy. Multiple anti-cancer treatments, including conventional chemotherapy, radiation, as well as targeted therapies such as histone deacetylase inhibitors and imatinib, have been found to activate autophagy as a pro-survival mechanism in cancer cells (Amaravadi and Thompson, 2007; Amaravadi et al., 2007; Kondo et al., 2005; Schoenlein et al., 2009). However, there is no pharmacological method currently available that can selectively inhibit autophagy. We have developed a series of small molecule inhibitors of autophagy, termed “spautins” for specific and potent autophagy inhibitors (Liu et al., 2011). Spautins target USP10 and USP13, two ubiquitin specific peptidases that regulate the ubiquitination and stability of Vps34 complexes, which are critical for autophagy initiation. Vps34 is the class III PI3 kinase that phosphorylates PI (phosphatidylinositol) to produce PI3P (phosphatidylinositol 3-phosphate). Treatment with spautin effectively reduces the levels of Vps34 complexes and PI3P, a key lipid signaling molecule essential for autopaghy, and consequently, leads to inhibition of autophagy. Since USP10 also mediates the deubiquitination of p53 (Yuan et al., 2010), spautins promote the degradation of p53 (Liu et al., 2011) and mutant p53. Our studies demonstrated that spautins show selective cytotoxicity to a subset of cancer cells while normal cells are relatively resistant to spautins (Liu et al., 2011). We will discuss our new data on the ability of spautin to induce the death of cancer cells in vitro and in vivo. Our study demonstrates a proof-of-principle for developing inhibitors of autophagy by targeting protein deubiquitination. Spautin family of autophagy inhibitors represent promising lead candidates for developing novel anti-cancer drugs. Reference: Amaravadi, R.K., and Thompson, C.B. (2007). The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 13, 7271-7279. Amaravadi, R.K., Yu, D., Lum, J.J., Bui, T., Christophorou, M.A., Evan, G.I., Thomas-Tikhonenko, A., and Thompson, C.B. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117, 326-336. Hoyer-Hansen, M., and Jaattela, M. (2008). Autophagy: an emerging target for cancer therapy. Autophagy 4, 574-580. Kondo, Y., Kanzawa, T., Sawaya, R., and Kondo, S. (2005). The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5, 726-734. Liu, J., Xia, H.G., Kim, M., Xu, L., Li, Y., Zhang, L., Yu, C., Norberg-Vakifahmetoglu, H., Zhang, T., Furuya, T., et al. (2011). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223-234. Lock, R., Roy, S., Kenific, C.M., Su, J.S., Salas, E., Ronen, S.M., and Debnath, J. (2010). Autophagy Facilitates Glycolysis During Ras Mediated Oncogenic Transformation. Mol Biol Cell 22, 165-178. Moreau, K., Luo, S., and Rubinsztein, D.C. (2010). Cytoprotective roles for autophagy. Curr Opin Cell Biol 22, 206-211. Schoenlein, P.V., Periyasamy-Thandavan, S., Samaddar, J.S., Jackson, W.H., and Barrett, J.T. (2009). Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy 5, 400-403. Yuan, J., Luo, K., Zhang, L., Cheville, J.C., and Lou, Z. (2010). USP10 regulates p53 localization and stability by deubiquitinating p53. Cell 140, 384-396. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY36-03. doi:1538-7445.AM2012-SY36-03