Abstract 1449: Aberrant expression of protein kinase D1 influences metabolic reconditioning in pancreatic cancer
Authors: Kumari Sonam , Khan Sheema , Yallapu Murali M. , Chauhan Subhash C. , Jaggi Meena 
Published: August 2018

Objective: Pancreatic cancer is one of the deadliest diseases, and the fourth most common cause of cancer-related deaths in the United States. Protein Kinase D1 (PKD1), a serine-threonine kinase, is an important modulator of several kinase signal transduction pathways. Although, PKD1 is known to be involved in pancreatic cancer pathogenesis, the underlying signaling mechanisms are largely unknown. Therefore, we investigated how PKD1 contributes to pancreatic tumor growth and progression. Our studies suggest a novel role of PKD1 in regulating glucose metabolism in pancreatic cancer, which drives pancreatic tumorigenesis and progression.

Methods: Glucose and Lactate assays were performed in pancreatic cancer cells following PKD1 transfection. Cell culture media was collected after 48 hrs to measure the amount of glucose consumption and L-lactate production on PKD1 expression in pancreatic cancer cells using in vitro assay kits (Cayman Chemicals). Immunoblotting and qRT-PCR assays were performed to assess the expression of protein and mRNA levels, respectively, of key signaling molecules in glucose metabolism in pancreatic cancer cells. Cell proliferation and colony forming assays were performed to determine the effect of PKD1 on cell proliferation and survival under both normoxic and hypoxic conditions. In vitro functional assays for investigating migration and invasion were performed using boyden chamber and Matrigel assays, respectively, under normoxic and hypoxic conditions.

Results: Our results show that PKD1 leads to altered glucose metabolism in pancreatic cancer cells. We observed increased amount of L-lactate production and glucose consumption on PKD1 expression in cells. This indicates the alterations in glucose metabolism associated with PKD1 expression in cells. These alterations were accompanied with enhanced expression of both protein and mRNA levels of Glut-1, HIF-1α, and KRAS, which are associated with glucose metabolism. These events were observed in both normoxic and hypoxic conditions, indicating that the PKD1 modulated events are independent of oxygen tension. Furthermore, we observed enhanced invasion and migration of pancreatic cancer cells on PKD1 expression, which was further increased by addition of lactate (an end product of aerobic glycolysis). Altogether, our studies indicate a role of PKD1 as a key regulator of the glucose metabolism and promoter of pancreatic cancer oncogenesis.

Conclusion: These results suggest that PKD1 plays an important role in metabolic reprogramming of pancreatic cancer cell metabolism to induce cancer growth and enhanced cellular invasion and motility. This is a first study that suggests the involvement of PKD1 in metabolic remodeling of pancreatic cancer cells leading to enhanced tumor growth and progression.

Citation Format: Sonam Kumari, Sheema Khan, Murali M. Yallapu, Subhash C. Chauhan, Meena Jaggi. Aberrant expression of protein kinase D1 influences metabolic reconditioning in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1449.