Targeting ATDC with PARP inhibitors in pancreatic cancer

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): We recently reported that ATDC (also known as TRIM29) is highly expressed in pancreatic cancers and that it exhibits oncogenic properties by promoting cell proliferation via the WNT/b-catenin pathway (Cancer Cell 15:207, 2009). Our preliminary results also show that ATDC protects pancreatic cancer cells against radiation and chemotherapy. The properties of growth promotion and resistance to therapy suggest that ATDC is an important therapeutic target. To better understand the function of ATDC and its role in resistance, we explored what proteins ATDC interacts with before and/or after exposure to ionizing radiation. Using immunoprecipitation assays we found that ATDC interacts with poly(ADP-ribose)polymerase1 (PARP1) and that this interaction is substantially increased following exposure to ionizing radiation. To investigate whether this interaction is dependent on the catalytic activity of PARP, we treated cells with PARP inhibitors and found surprisingly that this treatment lead to a marked loss of the cellular protein levels of ATDC. Furthermore, knockdown of Parp1 expression by siRNA resulted in reduced levels of ATDC indicating that PARP1 stimulates the expression of ATDC in pancreatic cancer cells. Importantly, our preliminary results suggest that PARP inhibition results in reduced proliferation and increased sensitivity to ionizing radiation of pancreatic cancer cells. We hypothesize that ATDC is a promising novel therapeutic target in pancreatic cancer because its inactivation may lead to both reduced tumor growth and sensitization to radiation therapy. Furthermore, we hypothesize that PARP inhibitors will target ATDC and selectively inhibit growth and sensitize ATDC-expressing pancreatic cancer tumors. PUBLIC HEALTH RELEVANCE: Pancreatic cancer has the worst outcome of any cancer and kills more than 30,000 people in the US annually. We recently found that the protein ATDC is expressed at abnormally high levels in pancreatic cancer and this overexpression promotes the growth and resistance of pancreatic tumors. Unexpectedly, we found that a class of chemotherapeutic drugs currently in clinical use reduces ATDC levels in pancreatic cancer cells and make them more sensitive to radiation. In this R21 proposal we will explore the mechanisms of how these drugs reduce ATDC levels and whether they will target ATDC in pancreatic tumors in laboratory mice.