TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 drive metabolic reprogramming with c‐MYC and NFkB activation in breast cancer

Abstract

Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells and loss of caveolin 1 (CAV1) with upregulation of monocarboxylate transporter 4 (MCT4) in fibroblasts. The mechanisms that drive metabolic coupling are poorly characterized. The effects of TIGAR on fibroblast CAV1 and MCT4 expression and breast cancer aggressiveness was studied using coculture and conditioned media systems and in‐vivo. Also, the role of cytokines in promoting tumor metabolic coupling via MCT4 on cancer aggressiveness was studied. TIGAR downregulation in breast carcinoma cells reduces tumor growth. TIGAR overexpression in carcinoma cells drives MCT4 expression and NFkB activation in fibroblasts. IL6 and TGFB drive TIGAR upregulation in carcinoma cells, reduce CAV1 and increase MCT4 expression in fibroblasts. Tumor growth is abrogated in the presence of MCT4 knockout fibroblasts and environment. We discovered coregulation of c‐MYC and TIGAR in carcinoma cells driven by lactate. Metabolic coupling primes the tumor microenvironment allowing for production, uptake and utilization of lactate. In sum, aggressive breast cancer is dependent on metabolic coupling.

Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer

“…Specifically, glycolytic metabolites fuel the biosynthesis of nucleosides and amino acids, essential for the synthesis of macromolecules required during proliferation. Moreover, glycolysis has been associated with the activation of signaling pathways involving proteins such as RAS (rat sarcoma virus oncogene), Myc (Myc proto-oncogene), TP53 (tumor protein suppressor p53), and HIF-1α (hypoxia inducible factor 1 subunit alpha), thereby promoting cancer development and progression [ 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, cancer cells display mitochondrial DNA mutations which induce mitochondrial dysfunction associated with tumor development, progression, and chemo-resistance.…”