The significantly enhanced lipogenesis is a metabolic hallmark of rapidly proliferating tumor cells. Although most normal cells acquire the bulk of their fatty acids from circulation, tumor cells synthesize more than 90% of required lipids de novo. The sterol regulatory element-binding protein 1 (SREBP1), encoded by SREBF1 gene, is a master regulator of lipogenic gene expression. Although it is known that SREBP1 and its target genes are overexpressed in a variety of cancers, the role of SREBP1 in endometrial cancer is largely unknown. Herein, we screened a panel of endometrial cancer specimen for their lipogenic gene expression by quantitative PCR and showed a significant increase in mRNA abundance of SREBF1, SREBF2, and FASN genes in cancer compared to normal endometrium. Immunohistochemical staining confirmed SREBP1 protein overexpression and further demonstrated increased nuclear distribution of SREBP1 in EC. SREBP1 promotes cellular proliferation in cell culture and enhances tumor growth in a xenograft model. Knockdown of endogenous SREPF1 gene impaired the viability of cells cultured in medium supplemented with lipid-depleted serum. BF175, a small molecule inhibitor designed to target SREBP1, repressed SREBP1-dependent gene expression and cell growth and induced EC cell death. We extended our observation to over 100 cancer cell lines from 12 different cancer types and showed promising results of BF175 in repressing tumor growth and inducing cell death. Together, this study established a role of SREBP1 in tumor growth and validated BF175 for its therapeutic effectiveness in targeting SREBP1 and lipogenesis to block cancer cell growth.
Citation Format: Chenguang Wang, Weihua Li, Jie Zhou, Yanhong Tai, Weiting Gu, Bhaskar C. Das, Junyuan Ji. Targeting lipogenic signaling to repress cancer cell growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5415. doi:10.1158/1538-7445.AM2013-5415