Abstract B56: Inactivation of LKB1-AMPK pathway is mediated by inflammation in pancreatic cancer

Abstract

Abstract Goal: The goal of this project is to determine if there is link between cancer cell metabolism and inflammation. LKB1is a known serine/threonine kinase tumor suppressor gene and it functions by sensing changes in cellular energy homeostasis and modulates anabolic and catabolic processes by activating its downstream kinase, AMP-activated protein kinase (AMPK). It is associated with Peutz-Jeghers syndrome, as well as various cancers including pancreatic cancer. Thus; it is a unique link between cell metabolism and inflammation. Hypothesis: Our hypothesis is that LKB1-AMK succumbs to inactivation processes because of increased NF-κB expression in pancreatic cancer cells and is associated with increased pancreatic cancer growth. Results: We tested five pancreatic cancer cells that express constitutive active NF-κB (pp65) and LKB1proteins by western blot analysis. In these cancer cells there was loss of active AMPK, phospho AMK (pAMPK) protein and its substrate pACC protein, suggesting a negative correlation between inflammation and loss of active AMPK. To strengthen this observation, we treated macrophage with LPS/IFNγ to create inflammatory environment and examined the protein levels of pp65, NF-κB regulated inflammatory gene (COX-2), pAMPK and pACC. We found that induction of pp65 and COX-2 are negatively correlated with pAMPK and pACC. To further support this observation we treated the pancreatic cancer cells with Metformin, a known activator of AMPK and our results clearly indicates that Metformin inhibits the proliferation of pancreatic cancer cells in a time-dependent manner. Metformin activates AMPK and ACC in pancreatic cancer cells. These data indicate that, compounds that activates LKB1-AMPK pathway can be beneficial in pancreatic cancer treatment. Citation Format: Sita Aggarwal, Qingxia Wang, Shailendra Giri, William Hansel. Inactivation of LKB1-AMPK pathway is mediated by inflammation in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B56.