Abstract
Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression. We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells. NNMT depletion reversed metabolic plasticity in glucose-restricted cells and prevented de novo formation of glucose-restricted colonies. In addition to its role in glucose independence, we found that NNMT was required for other ZEB1-induced phenotypes, such as increased migration. NNMT protein levels were also elevated in metastatic and recurrent tumors compared to matched primary carcinomas, while normal ovary and fallopian tube tissue had no detectable NNMT expression. Our studies define a novel ZEB1/NNMT signaling axis, which elicits mesenchymal gene expression, as well as phenotypic and metabolic plasticity in ovarian cancer cells upon chronic glucose starvation. Understanding the causes of cancer cell plasticity is crucial for the development of therapeutic strategies to counter intratumoral heterogeneity, acquired drug resistance and recurrence in high-grade serous ovarian cancer (HGSC).
Highlights
Cellular energy metabolism is one of the first processes altered during neoplastic transformation and its deregulation is one of the emerging hallmarks of cancer [1, 2]
We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells
While ZEB1 is a known inducer of epithelial-to-mesenchymal transition (EMT), we find that EMT is not required for glucose independence
Summary
Cellular energy metabolism is one of the first processes altered during neoplastic transformation and its deregulation is one of the emerging hallmarks of cancer [1, 2]. Proliferating cancer cells increase glucose uptake and undergo aerobic glycolysis (“Warburg effect” [1, 3, 4]) in order to meet their increased metabolic demands for the biosynthesis of nucleolipids, lipids, amino acids and NADPH [5]. Since the main role of bevacizumab is to deprive the tumor of its blood supply in order to induce cancer cell starvation and apoptosis, bevacizumab-treated cancers are exposed to nutritional stress, such as glucose deprivation Taken together, these data suggest that some regions of advanced solid tumors, including HGSC, are deprived of glucose. A study on phenotypic consequences of chronic glucose withdrawal on ovarian cancer cells has not been performed
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