TRIP6 Regulates p27^KIP1 To Promote Tumorigenesis

Abstract

TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving 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 lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27 KIP1 expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27 KIP1 expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.T hyroid hormone receptor-interacting protein 6 (TRIP6) is a zyxin-related adaptor protein and focal adhesion molecule (1). Through its three LIM domains, PDZ-binding motif, Crk SH2-binding motif, and several putative SH3-binding domains, TRIP6 associates with a variety of molecules from the cell surface to the nucleus to regulate actin reorganization, focal adhesion assembly/disassembly, cell migration/invasion, antiapoptotic signaling, and transcriptional control. Notably, TRIP6 binds to lysophophatidic acid (LPA) receptor 2 (LPA 2 ) and the Fas/CD95 receptor to promote LPA-and Fas ligand-induced cell migration in a c-Src-dependent manner (2-4). TRIP6 can also regulate prosurvival signaling via activation of NF-B, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/ AKT (3, 5), and nuclear TRIP6 acts as a transcriptional coregulator of AP-1 and NF-B (6). These data suggest that TRIP6 functions at a point of convergence of multiple signaling pathways critical for cancer development.We recently showed that TRIP6 is overexpressed in glioblastomas (3). By analyzing the survival of glioma patients, we found that the increased expression level of TRIP6 correlates significantly with poor clinical outcomes. Although these findings implicate a role for TRIP6 in cancer progression, the precise function of TRIP6 in tumorigenesis remains largely unknown. To address this issue, we examined the effect of TRIP6 knockdown on the proliferation of glioblastoma and ovarian cancer cell lines that express TRIP6 at high levels. These studies reveal a novel role for TRIP6 in tumorigenesis by promoting the loss of nuclear p27 KIP1

Overexpression of TRIP6 promotes tumor proliferation and reverses cell adhesion-mediated drug resistance (CAM-DR) via regulating nuclear p27Kip1 expression in non-Hodgkin’s lymphoma

“…Previous study reported that TRIP6 can bind to p27 Kip1 and promote its phosphorylation at T157, leading to cytosolic mislocalization [10]. In this report, we showed that adhesion to FN decreased TRIP6 expression, thereby increasing nuclear p27 Kip1 expression via decreasing phosphorylation of p27 Kip1 at T157.…”

“…Previous study demonstrated that knockdown of TRIP6 in glioblastoma or ovarian cancer can elevate nuclear p27 Kip1 expression [10]. As we know, adhesion of tumor cells to FN can induce cell cycle arrest and protect tumor cells from chemotherapeutic drug-induced apoptosis via increasing nuclear p27 Kip1 protein expression [5,6].…”

“…Overexpression of TRIP6 promotes invasiveness by enhancing NF-κB transcriptional activity in colorectal tumors [9]. TRIP6 knockdown inhibits tumor proliferation by restoring nuclear p27 Kip1 in glioblastoma and ovarian carcinoma [10]. TRIP6 can also regulate the migration of a variety of cancer cells, including ovarian carcinoma [11], lung carcinoma [12], and nasopharyngeal carcinoma [13].…”

Gene Expression Profiling of Desmoid Tumors by cDNA Microarrays and Correlation with Progression-Free Survival

“…TRIP6 can also regulate prosurvival signaling via activation of NF-kB, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/AKT, and nuclear TRIP6 acts as a transcriptional coregulator of AP-1 and NF-kB. These data suggest that TRIP6 functions at a point of convergence of multiple signaling pathways critical for cancer development (29). Thus, TRIP6 acts as an oncogene that partially accounts for the autonomous migratory, invasive, and proliferative properties of Ewing sarcoma cells independent of EWS/FLI1.…”

“…Moreover, in nasopharyngeal cancer cells (NPC), TRIP6 overexpression/knockdown results in significant enhancement/inhibition of NPC cell migration, respectively (31). Finally, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27 (KIP1) expression and impairs tumor proliferation and may have a significant impact on enhanced NF-kB activity, resistance to apoptosis, and Fas-mediated cell invasion in glioblastomas (29,32). Paradoxically, in desmoid tumors, TRIP 6 was overexpressed in the good outcome group.…”