Abstract
MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in primary tumor tissue specimens from human pancreatic adenocarcinoma cancer patients. Overall, our results demonstrate that MUC16 plays an important role in metabolic reprogramming of pancreatic cancer cells by increasing glycolysis and enhancing motility and invasiveness.
Highlights
Pancreatic cancer is one of the deadliest malignancies and is the fourth leading cause of cancerrelated deaths in the United States [1]
Because growth and invasive properties of most cancer cells significantly depend on their glycolytic capacity [22], we investigated the effect of MUC16 knockdown on glucose uptake of pancreatic cancer cells
Keeping in view the oncogenic functions of MUC16, we investigated its role in metabolic reprogramming of pancreatic cancer cells
Summary
Pancreatic cancer is one of the deadliest malignancies and is the fourth leading cause of cancerrelated deaths in the United States [1]. Despite substantial progress in the understanding and therapy of pancreatic cancer, the overall 5-year survival rate remains about 5% [3]. The lethal nature of pancreatic cancer is mainly correlated with its late diagnosis, high metastatic capacity to nearby organs, and resistance to therapeutic agents [4]. There is an urgent need for a better understanding of the molecular mechanisms of pancreatic cancer pathogenesis that contribute to aggressiveness, metastasis and poor prognosis among patients. Several oncogenes and tumor suppressors have been reported to play a role in the origin and pathogenesis of pancreatic cancer. A family of high molecular weight and heavily glycosylated proteins, are known to play important roles in pancreatic cancer pathogenesis. Mucin family members are involved in oncogenesis, metastasis and therapeutic resistance in pancreatic cancer [6, 7]. Among the several members of the mucin family, expression of MUC1, www.impactjournals.com/oncotarget
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