Abstract 4375: Overexpression of CD36 promotes colorectal cancer cell proliferation via upregulation of survivin

Abstract

Abstract Altered fatty acid metabolism has is a hallmark of cancer and continues to be a potential target for therapeutic intervention in cancer. Fatty Acid Translocase (CD36), a multifunctional glycoprotein, has been shown to have an important role in fatty acid metabolism as a fatty acid transporter. Fatty Acid Synthase (FASN), a critical enzyme involved in de novo lipogenesis, has been shown to be upregulated and associated with a poor prognosis in many cancers including colorectal cancer (CRC). However, the role of CD36 in 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 functional importance of CD36 in CRC and (ii) investigate potential relationships between CD36 and FASN expression in CRC cells. METHODS. Expression of CD36 and FASN was assessed by immunohistochemistry (IHC) using a CRC TMA with 2 sets of tissues: (i) Primary tumors with matched normal colon tissue; [n=56]; (ii) primary and metastatic tumors (liver [n=12] and lung metastasis [n=5]) with matched normal colon. Cellular proliferation was assessed in control and CD36 shRNA knockdown CRC cells, and in primary CRC cells established from patient derived xenografts treated with CD36 inhibitor Sulfo-N-succinimidyl oleate (SSO) in combination with FASN inhibitor TVB-3664. CD36 knockdown was confirmed by qRT-PCR. Expression of pro-survival and apoptotic markers was assessed via western blot in CD36 knockdown and overexpression CRC cells, as well as CD36+ and CD36- isogenic cells. CD36 localization was assessed via confocal imaging. RESULTS. We found that CD36 is overexpressed in primary tumors as compared to normal colon mucosa and its expression positively correlates with expression of FASN. Cellular proliferation was significantly reduced when CD36 was inhibited by SSO and a further reduction in proliferation was observed when SSO treatment was combined with TVB-3664. Knockdown and chemical inhibition of CD36 decreased expression of survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, which was shown to promote cancer cell survival in many tumor types. Conversely, overexpression of CD36 increased survivin expression in CRC cells. Additionally, shRNA knockdown of FASN induced CD36 expression in CRC cells. Immunofluorescence imaging of primary CRC cells treated with TVB-3664 showed an upregulation of membrane-bound CD36. CONCLUSION. Our studies indicate that CD36 upregulation is associated with an increase in cellular proliferation via upregulation of survivin in CRC cells. The correlation between CD36 expression and FASN suggest a connection between CD36 and de novo lipid synthesis. Furthermore, a decrease in FASN expression is associated with CD36 induction, suggesting a possible mechanism of resistance to FASN inhibition. Better understanding of the role of CD36 in CRC may provide new therapeutic approaches for treatment of CRC patients Citation Format: James Drury, Naser Jafari, B. Mark Evers Evers, Yekaterina Y. Zaytseva. Overexpression of CD36 promotes colorectal cancer cell proliferation via upregulation of survivin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4375.