Abstract 4399: MUC13 induced NFκB activation regulates metabolic reprograming by promoting its crosstalk with GLUT-1 receptor
Authors: Kumari Sonam , Khan Sheema , Gupta Subash C. , Kashyap Vivek K. , Yallapu Murali M. , Chauhan Subhash C. , Jaggi Meena 
Published: July 2017

Abstract
Objective: Pancreatic cancer (PanCa) is the fourth most common cause of cancer-related deaths in the US. MUC13, mucin is aberrantly expressed in PanCa and promotes tumor growth and progression. Herein, we investigate the fundamental role of MUC13 in glucose metabolism and delineate the molecular interplay of various molecules governing MUC13 mediated metabolic reprograming that may be involved in pancreatic tumor maintenance.
Methods: MUC13 expressing (Panc-1) and knockdown PanCa cells (HPAF-II) were generated for the study. Immunoblotting and qRT-PCR assays were performed to assess the expression of protein and mRNA levels, respectively, of key signaling molecules involved in glucose metabolism of PanCa. MUC13 and Glut-1 interaction was studied using reciprocal co-immunoprecipitation, immunofluorescence, proximity ligation, Western blotting, co-capping assays in cell lines. Lactate and glucose assays were performed using commercially available kits. In vitro functional assays using wound healing scratch assay (migration), and cell Matrigel assay (invasion) were performed in presence or absence of Lactate and 2DG supplementation.
Results: Our results demonstrate that MUC13 expression leads to the TNF-induced activation/nuclear translocation of NFκB p-65 and phosphorylation of IkB which in turn upregulates additional key proteins, Glut-1, c-Myc, Bcl-2. This recruits the Glut-1 to MUC13, wherein MUC13 functionally interacts with Glut-1 and stabilizes it, initiating downstream events that result in altered glucose metabolism. MUC13 expression in PanCa cells increases glucose uptake, lactate secretion which is reduced upon MUC13 knockdown. Additionally, MUC13 mediates increased cell migratory and invasion potential which can be potentiated by supplementing the culture media with lactate, an end product of aerobic glycolysis. However, treatment of cells with NFκB inhibitor, Sulfasalazine, inhibits the MUC13 and Glut-1 interaction and abrogates all these events associated with glucose metabolism.
Conclusion: These outcomes from our study suggest that MUC13 plays an important role in metabolic reprogramming of PanCa cells metabolism to induce cancer growth and enhanced cellular invasion and motility. NFκB acts downstream of MUC13 to coordinate the events leading to its interation with Glut-1 and metabolic reprogramming. Overall, these findings illustrate mechanisms by which MUC13 coordinates the shift in metabolism to sustain cancer growth and invasion in PanCa.
Citation Format: Sonam Kumari, Sheema Khan, Subash C. Gupta, Vivek K. Kashyap, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi. MUC13 induced NFκB activation regulates metabolic reprograming by promoting its crosstalk with GLUT-1 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4399. doi:10.1158/1538-7445.AM2017-4399