Abstract #LB-274: Role of ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) in cell adhesion, secondary homing and recurrence in presence of lysophosphatidic acid and paclitaxel.

Ovarian cancer remains the most lethal gynecologic malignancy. Despite the introduction of taxanes in the 1980\#8217;s, overall survival for ovarian cancer has remained poor, and management of late stage or recurrent disease is a continuing problem. We have reported (Gyn. Onc. 2008) that ovarian cancer immunoreactive antigen domain 1 (OCIAD1) is up-regulated in late stage disease when compared to the paired primary tumor and that OCIAD1 plays a role in LPA induced cell adhesion. Results also indicated that paclitaxel sensitivity was inversely correlated with OCIAD1 expression in several ovarian cancer model systems. In this study we have tested the role of OCIAD1 in the presence of 18:1 lysophosphatidic acid (LPA) that is omnipresent in the blood and ascites of ovarian cancer patients for effects on paclitaxel sensitivity. The model system developed to test the role of OCIAD1 was an in vitro secondary cell homing assay on matrigel to mimic recurrent ovarian cancer. In contrast to cells transfected with scrambled siRNA (gain of function), OCIAD1 targeted siRNA (loss of function) treated cells lacked the ability to form secondary colonies in presence of paclitaxel. In addition to stimulating OCIAD1 phosphorylation, LPA also upregulated OCIAD1 expression in the nucleus of cells within 2 hrs of treatment and OCIAD1 was found to subsequently redistribute in the cytosol within 24 hrs. Using both small molecule inhibitors and genetic techniques our results demonstrate that LPA induced OCIAD1 up-regulation is mediated through the LPA - MKK6 - p38 pathway. Cycloheximide treatment coupled with quantitative PCR results indicated that MKK6 stimulated OCIAD1 upregulation was transcriptionally regulated. This is the first report demonstrating that OCIAD1 function can be upregulated by LPA through the MKK6-p38 pathway and OCIAD1 up-regulation can result in cells increased ability to tolerate chemotherapeutic insults and survive, a hallmark often leading to late stage disease and recurrence. These results raise the possibility of using OCIAD1 inhibition strategies to improve paclitaxel sensitivity for late stage ovarian cancer management. Further, studies using in vivo models of ovarian cancer developed in our laboratory are currently being evaluated to test whether elevated OCIAD1 levels can lead to increased metastasis and recurrence. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-274.