REGULATION OF TUMOR DEVELOPMENT BY THE UBIQUITIN LIGASE ITCH

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite progress made in screening, early detection, and removal of precancerous polyps, colorectal cancer remains the second leading cause of cancer death in all Americans. Consequently, much research is dedicated to identifying tumor-specific molecules that might be targeted in advujant therapies and could be readily combined with currently used chemotherapy regimes. We present here the hypothesis that ITCH, a member of the Nedd4-like family of ubiquitin ligases, is a viable candidate for neoadjuvant therapies. It has been shown to be amplified in anaplastic thyroid carcinoma, and in vitro inhibition of Itch potentiates the effect of chemotherapeutic drugs in a variety of cancer cell lines by enhancing apoptosis in response to drug treatment. We demonstrate that Itch plays a critical role in the in vivo initiation of intestinal adenomas, and ApcMin/+ mice lacking Itch have a 71% reduction in their tumor burden. We hypothesize that epithelial cells lacking Itch (particularly tumor cells) are more sensitive to TXNIP-, p63-, or p73-mediated apoptosis. We will test this hypothesis by 1) determining the role played by Itch in both the epithelium and in the immune system using bone marrow transplantation; 2) delineating the window when ApcMin/+ -derived tumors are sensitive to the loss of Itch using a conditional knockout approach; and 3) characterizing the expression of bona fide Itch targets, Txnip, p63, and p73 in normal vs. tumor vs. 5-fluorouracil treated tissues using Q-PCR, Western blotting, and immunohistochemistry analysis. The data generated herein will provide critical rationale for developing this new potential adjuvant therapy.