Abstract 51: Role of MUC13 as non-hypoxic stimuli inducing HIF-1α in pancreatic cancer under normoxia
Authors: Kumari Sonam , Khan Sheema , Chauhan Subhash , Jaggi Meena 
Published: July 2016

Objective: Pancreatic cancer is the fourth most common cause of deaths occurring due to cancer, with an overall survival rate of just 5%. MUC13, a transmembrane mucin, is aberrantly expressed in pancreatic cancer, while an altered glucose metabolism is known to facilitate cancer cell survival and proliferation. Hypoxia-inducible factor 1 α (HIF-1 α) plays an important role in reprogramming of cancer cell metabolism by activating the transcription of genes which encode glucose transporters and enzymes involved in glycolysis. Recent reports suggest that several non-hypoxic stimuli such as lipopolysaccharides, thrombin, and angiotensin II can also increase HIF-1α under normoxia. Herein, we investigated the effects of MUC13 expression on glucose metabolism and elucidated underlying signaling mechanisms that might be involved in this process.

Methods: MUC13 null pancreatic cancer Panc-1 cells were used for the study. Glucose and Lactate assay were performed in Panc-1 cells stably expressing MUC13 (Panc-1-M13) and vector (Panc-1-V). Cell culture media after 48 hrs was collected to measure the amount of unused glucose and L-lactate concentration using glucose and Lactate assay kits. Immunoblot and semi-quantitative PCR analyses were performed to check the expression of protein and mRNA levels, respectively. Cell proliferation and colony forming assays were performed to determine the effect of MUC13 on cellular growth and cell survival.

Results: Our results demonstrate that MUC13 acts as a modulator of the glucose metabolism in pancreatic cancer cells by regulating the expression and activity of hypoxia-inducible factor-1α (HIF-1α) and its downstream targets. We observed increased amount of L-lactate production and glucose consumption in Panc-1-M13 cells as compared to Panc-1-V cells. This facilitates metabolic alterations and help tumor cells survive and proliferate under these conditions as indicated by increased cellular growth pattern in Panc-1-M13 cells. Our results demonstrate increased expression of the downstream targets of HIF-1α, such as cell regulatory (c-Myc), and cell survival (Bcl-2) proteins, while decreased the expression of tumor suppressor/cell cycle inhibitor (p-27) proteins in Panc-1M13 cells. Additionally, an increase in the expression of a critical downstream target of HIF-1α, Glut-1 was observed in Panc-1-M13 cells.

Conclusion: Our studies indicate that MUC13 acts as a key regulator of the metabolic process and facilitates metabolic alterations in the non-hypoxic environment that help tumor cells survive and proliferate under these conditions. However, further studies are required to elucidate detailed molecular mechanisms that are involved in MUC13 mediated metabolic remodeling in pancreatic cancer cells.

Citation Format: Sonam Kumari, Sheema Khan, Subhash Chauhan, Meena Jaggi. Role of MUC13 as non-hypoxic stimuli inducing HIF-1α in pancreatic cancer under normoxia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 51.