Abstract A08: The role of branched-chain amino acid metabolism in Myc-driven malignancies

Cancer cells have high metabolic demands. Myc oncoproteins function as transcription factors and are overexpressed in a number of human malignancies. Myc induces the transcription of a number of genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are dependent on and utilize L-glutamine to feed carbon intermediates into the Krebs Cycle. We reasoned that Myc would also control the catabolism of BCAA, which also provides key metabolic intermediates, specifically acetoacetate, acetyl-CoA, proprionyl-CoA, NADH and FADH2. Consistent with this notion, expression analysis of premalignant and neoplastic B cells of Eμ-Myc transgenic mice, a validated model of human B cell lymphomas with Myc involvement, showed elevated mRNA and protein levels of BCAT1, which is a bona fide Myc transcription target and the first enzyme in BCAA catabolism. Further, elevated levels of several other enzymes involved in BCAA catabolism manifest in Eμ-Myc B cells. To assess the role of BCAT1 in tumor cell growth and survival, human B cell lymphoma and ovarian tumor cell lines that express high levels of BCAT1 were engineered to inducibly express shRNA that selectively silences BCAT1 expression. Notably, BCAT1 knockdown impaired tumor cell growth and survival, and long-term clonogenic growth. Moreover, treatment of Eμ-Myc B cel...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research