Translocase of the Outer Mitochondrial Membrane 20 (TOMM20) and TP53 Inducible Glycolysis and Apoptosis Regulator (TIGAR)) Drive Metabolic Reprogramming in Cancer
Abstract
It is well established that cancer cells undergo metabolic reprogramming to meet the energy demands of cell growth. Initially it was thought that cancer cells preferentially utilize glucose and undergo aerobic glycolysis, which refers to cytosolic glucose catabolism to lactate even in the presence of oxygen. However, cancer cells utilize mitochondrial metabolism in addition. Glucose, as well as alternative substrates such as lactate, ketone bodies, acetate, and glutamine, can fuel mitochondrial metabolism in cancer. Metabolic heterogeneity occurs when cells such as cancer associated fibroblasts (CAFs) exhibit glycolytic metabolism and cancer cells utilize mitochondrial oxidative phosphorylation (OXPHOS) metabolism. High energy metabolites can be transported to the cancer cells for mitochondrial metabolism. Metabolic reprogramming and metabolic heterogeneity have been described in many human cancer types, but the mechanisms that drive these changes in metabolism and cancer aggressiveness remain poorly characterized. Chondrosarcomas are resistant to radiation and chemotherapy agents, but the molecular and metabolic mechanisms that drive this aggressive phenotype remain poorly characterized. We studied the role of a subunit of the mitochondrial protein import machinery in chondrosarcoma metabolism, aggressiveness and therapy resistance. We determined that high-grade human chondrosarcoma tumors have higher expression of the mitochondrial import protein, translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), compared to low-grade tumors. TOMM20 overexpression in chondrosarcoma cells drives proliferation, resistance to apoptosis and chemotherapy, tumor growth and OXPHOS. In conclusion, TOMM20 drives chondrosarcoma aggressiveness and mitochondrial metabolism. In the second part of this thesis, we aimed to determine the mechanisms by which TP53 inducible glycolysis and apoptosis regulator (TIGAR) promotes metabolic heterogeneity with the induction of OXPHOS metabolism in cancer cells while inducing glycolysis in fibroblasts. We examined the effects of TIGAR in carcinoma cells on breast cancer aggressiveness and the effects of cancer cell TIGAR on CAFs. TIGAR expression in cancer cells leads to CAF loss of caveolin 1 (CAV1) and upregulation of Monocarboxylate transporter 4 (MCT4), both of which contribute to the induction of metabolic heterogeneity. The ability of TIGAR to induce larger tumor size is abolished in an MCT4 knockout (MCT4-/-) background. Also, we discovered co-regulation of c-Myc and TIGAR driven by lactate. In addition, metabolic heterogeneity induces metabolic priming in the tumor microenvironment allowing for production, uptake, and utilization of lactate. In conclusion, TIGAR’s ability to induce cancer aggressiveness is dependent upon its ability to induce metabolic heterogeneity.
Subject Area
Oncology|Biochemistry|Biology
Recommended Citation
Roche, Megan Elizabeth, "Translocase of the Outer Mitochondrial Membrane 20 (TOMM20) and TP53 Inducible Glycolysis and Apoptosis Regulator (TIGAR)) Drive Metabolic Reprogramming in Cancer" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI29328241.
https://jdc.jefferson.edu/dissertations/AAI29328241
