Abstract 1443: Overexpression of CD36 promotes tumorigenesis in colorectal cancer

Abstract

Abstract Fatty acid translocase (CD36), a multifunctional glycoprotein, has an important role in fatty acid metabolism as a fatty acid receptor and transporter. The presence of CD36 positive metastasis-initiating cells correlates with a poorer prognosis in glioblastoma and oral carcinoma. Fatty acid synthase (FASN), a critical enzyme involved in de novo lipogenesis, is upregulated and associated with poorer prognosis in many cancers including colorectal cancer (CRC). The role of CD36 in primary and metastatic CRC as well as its relation to de novo fatty acid synthesis is not understood. The purpose of our study was: (i) to determine the role of CD36 in primary and metastatic CRC, and (ii) to delineate the association of CD36 expression with FASN as a possible mechanism of resistance to FASN inhibition. METHODS. Expression of CD36 and FASN was assessed in a CRC tumor microarray (matched normal colon and primary tumor; 56 cases) as well as matched normal colon, primary and metastatic tumors (liver [n=12] and lung metastasis [n=5]) by immunohistochemistry. CD36 expression was analyzed in control and FASN shRNA knockout CRC cells and tissues from APC/FASN/CRE mouse models by western blot. Cell proliferation was assessed in primary CRC cells established from patient derived xenografts (PDX) treated in combination with Sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, and FASN inhibitor TVB-3664. CD36 expression levels in primary and metastatic PDX derived CRC cells were analyzed via western blot and immunofluorescence imaging. RESULTS. CD36 is overexpressed in primary tumors as compared to normal colon mucosa and its expression positively correlates with expression of FASN. Cell proliferation was significantly reduced when CD36 was inhibited by SSO and a further reduction in cell proliferation was observed when SSO treatment was combined with TVB-3664. Treatment with SSO induced apoptotic markers such as cleaved capspase-3 and decreased survivin. Western blot analysis of primary and metastatic CRC cells showed an upregulation of CD36 expression in the metastatic CRC cells. Additionally, FASN shRNA knockdown of FASN in CRC cells and Cre recombinase-mediated intestinal deletion of FASN in an APC/FASN/CRE mouse model led to an induction of CD36 expression. Immunofluorescence imaging of primary CRC treated with TVB-3664 showed an upregulation of membrane bound CD36. CONCLUSION. CD36 upregulation is associated with CRC progression and inhibition of CD36 decreases proliferation and survival of primary CRC cells. Correlation between expression of CD36 and FASN suggests an interconnection between CD36 and de novo lipid synthesis. Furthermore, a decrease in FASN expression is associated with an induction of CD36, suggesting a possible mechanism of resistance to FASN inhibition. Better understanding the role of CD36 may provide new therapeutic approaches for treatment of CRC patients. Citation Format: James M. Drury, Naser Jafari, B Mark Evers, Yekaterina Y. Zaytseva. Overexpression of CD36 promotes tumorigenesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1443.