Abstract POSTER-BIOL-1333: TRIP6 regulates p27KIP1 to promote ovarian tumorigenesis

Although the nuclear p27 KIP1 functions as a negative regulator of G1/S cell cycle progression by binding to and inhibiting cyclin-CDK complexes, the cytosolic p27 KIP1 has been shown to promote adhesion disassembly and tumor invasion. Loss of nuclear p27 KIP1 and cytosolic mislocalization of p27 KIP1 are frequently found during cancer progression, and these events correlate with poor clinical outcome in many types of cancers, including ovarian cancer. However, the mechanisms underlying this dysregulation are not yet fully understood. TRIP6 is an adaptor protein that is highly expressed in ovarian serous cystadenocarcinoma. It serves as a platform to recruit a number of molecules, such as NF-κB p65, c-Src, p130cas, Crk, LPA2 and Fas/CD95 receptors, to promote cell motility and antiapoptotic signaling. Using an ovarian cancer xenograft mouse model, we find that TRIP6 knockdown significantly reduces ovarian tumor proliferation. We determine that this effect is in part through the regulation of p27 KIP1 . Our data show that TRIP6 serves as a bridge to promote the recruitment of p27 KIP1 to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT, and facilitates AKT-mediated recognition and phosphorylation of p27 KIP1 specifically at T157, thereby promoting the cytosolic mislocalization of p27 KIP1 . This is required for p27 KIP1 to enhance LPA-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27 KIP1 expression through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in ovarian cancer xenografts restores nuclear p27 KIP1 expression and impairs tumor proliferation. Since the expression of TRIP6 and the activity of AKT are significantly higher in ovarian cancer, restoring the expression of nuclear p27 KIP1 and inhibiting the migratory effect of phospho-T157-p27 KIP1 by targeting TRIP6 may prove to be an effective approach to reduce ovarian cancer progression. Citation Format: Fang-Tsyr Lin, Victor T. G. Lin, Vivian Y. Lin, Yun-Ju Lai, Chen-Shan Chen, Kang Liu, Weei-Chin Lin. TRIP6 regulates p27 KIP1 to promote ovarian tumorigenesis [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1333.