Abstract 1166: ASCT2: A novel metabolic target for cancer therapy

Uncontrolled proliferation of cancer cells is often fueled by the deregulation of various cellular signaling pathways. Such deregulation also frequently rewires the metabolism of cancer cells in order to meet their increased need for energy and nutrients required for growth and proliferation. In the process, tumor cells produce high levels of anabolic intermediates required for biosynthesis of macromolecules and redox homeostasis. Many of these building blocks are derived from tri-carboxylic acid cycle (TCA) intermediates that need to be replenished in a process called anapleurosis. Glutaminolysis, the process in which glutamine (Gln) is converted into TCA intermediates by glutaminase is one of the key pathways that feeds anapleurosis in cancers. Many tumor cell lines fail to grow in the absence of glutamine and are therefore addicted to this nutrient. Glutamine is a preferred substrate for ASCT2, a member of ASC family of amino acid transporters, and thus this transporter may play a role in this addiction. We screened a variety of cancer cells for their dependence on Gln and determined that a significant subset of cell lines require this important nutrient. Biochemical experiments indicated that the ASCT2 family of proteins is the main driver of Gln transport. In agreement with these findings, shRNA-mediated knock down of ASCT2 significantly inhibited 14 C-Gln uptake and tumor cell proliferation. Expression of an shRNA-resistant ASCT2 gene rescued both the inhibition of cell proliferation and transport of Gln. Furthermore, stable knockdown of ASCT2 induced autophagy and significantly slowed growth in vivo of various tumor types such as colon carcinoma, prostate carcinoma, and in neuroblastoma. The above findings identify ASCT2 as an attractive target for therapeutic intervention. Note: This abstract was not presented at the meeting. Citation Format: Nabendu Pore, Wanda King, Kristen Lekstrom, Susan Wilson, Robert Hollingsworth, David A. Tice, Emil Michelotti. ASCT2: A novel metabolic target for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1166. doi:10.1158/1538-7445.AM2015-1166