Abstract LB-34: Investigating novel biological functions of tankyrases in cancer

Abstract

Abstract Tankyrases (TNKS1 and TNKS2) are enzymes that catalyze the addition of poly(ADP-riboses) on acceptor proteins. Through poly(ADP-ribosylation), TNKS regulate the activity and/or stability of their substrates via different mechanisms. A number of TNKS substrate proteins of diverse biological functions have been reported. More recently, in silico analysis using consensus-derived TNKS binding motif predicts a wide range of proteins may be targeted by TNKS, supporting that TNKS is involved in the regulation of diverse cellular processes. In particular, TNKS have been linked to telomere elongation, Wnt signaling and spindle assembly during mitotic progression, functions that are essential for cell proliferation. Hence, TNKS could be potential molecular targets for anti-cancer therapeutics. Using highly potent and specific TNKS inhibitors or depletion of TNKS by RNAi, we have identified several cancer models which growth is dependent on TNKS activity. In one of the TNKS-dependent cancer models, RERF-LC-MS, our studies demonstrate depletion of β-catenin does not impair cell proliferation. These data suggest TNKS regulate cell proliferation in this model via Wnt-independent functions. In an effort to elucidate the mechanism underlying RERF-LC-MS growth dependence on TNKS, we tested the hypothesis whether TNKS inhibition leads to aberrant spindle formation. We observed that inhibition of TNKS increases the formation of multipolar spindles in mitotic cells. We are currently testing whether this is mediated by NuMA, a well described substrate of TNKS whose function is required for spindle integrity. In addition, we are performing proteomic studies to identify novel binding partners of TNKS that would help to unravel novel partners of TNKS in mitosis and their functions in mediating cancer cell dependence on TNKS. Overall, this work will further increase our understanding of TNKS biology in cancer, and will impact on how we could best target TNKS as a novel anti-cancer treatment. 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 LB-34. doi:1538-7445.AM2012-LB-34