| Description |
Metabolism is a fundamental process of all living organisms. Nutrient acquisition and utilization are tightly controlled for coordinated cell growth and execution of physiological function. However, cancer cells reprogram their metabolism to meet the increased bioenergetic, biosynthetic, and redox demands to sustain rapid growth and proliferation, which is now recognized as a hallmark of cancer. The cancer-specific metabolism is characterized by upregulation of glycolysis and biosynthetic pathways, each of which is fueled by glucose-derived carbons. Thus, nutrient use must be coupled with nutrient availability to sustain the unbridled growth of cancer cells. Thioredoxin-Interacting Protein (TXNIP) is a potent inhibitor of glucose uptake and aerobic glycolysis, and is downregulated in a number of human cancers. Transcription of the TXNIP gene is dependent on the MondoA transcription factor and is regulated by a plethora of cellular and environmental cues. For example, TXNIP transcription is induced by stress conditions, such as low pH and endoplasmic reticulum (ER) stress. Consequently, the TXNIP-dependent restriction of glucose uptake halts cell growth until cellular homeostasis is restored. On the other hand, TXNIP transcription is suppressed by pro-growth signals such as PI3K, AKT, mTOR, and Myc activation, which allows for sufficient glucose uptake to sustain the glycolytic and anabolic metabolism driven by oncogene activation. Here we show that oncogenic Ras downregulates TXNIP mRNA and protein expression. Specifically, Ras suppresses translation elongation of TXNIP mRNA by targeting the N-terminus of nascent TXNIP peptide chain as it exits the ribosome exit tunnel. Acute growth factor signaling also downregulates TXNIP expression. It does so, in contrast, by upregulating TXNIP protein degradation and inhibiting TXNIP protein synthesis. Lastly, we show that stringent metabolic stress activates MondoA-dependent TXNIP transcription, and the increased TXNIP protein level leads to decreased glucose uptake. However, the stress-induced TXNIP expression and the consequent restriction in glucose uptake are abrogated by oncogenic Ras. In sum, our work provides mechanistic detail for the role of the MondoA-TXNIP circuit as a metabolic checkpoint in coordinating cell growth in response to oncogenic signaling and microenvironmental stresses. |
