Abstract 5078: Modulation of glucose metabolism and lactate efflux in tumors by bitter melon juice in its efficacy against pancreatic cancer

Pancreatic cancer (PanC) is currently ranked as the fourth leading cause of cancer-related deaths across the United States. The dismal statistics for the year 2018 estimates about 55,440 new incidences and 44,330 PanC-associated fatalities in men and women combined, with a 5-year survival rate of less than 10%. PanCs possess a very intricately designed metabolic profile favoring excess aerobic glycolysis in addition to altered glutamine metabolism, contributing to tumor cell proliferation and PanC progression. Targeting metabolic phenotype in PanC with natural/diet-derived agents has immense scope for better non-toxic intervention, improved overall survival and quality of life; the major concerns with the use of frontline PanC chemotherapeutics. Herein, we utilized bitter melon juice (BMJ), a natural agent, which we recently reported to possess anticancer potential via targeting PanC stem cell and bulk cell populations and exerting a role in elevating drug sensitivity of gemcitabine resistant PanC cells. The established role of BMJ in activating master metabolic regulator APMK in PanC cells served as a basis for pursuing deeper investigation into the underlying metabolic alterations leading to BMJ efficacy in PanC. We investigated the comparative metabolic profiles of PanC cells with differential KRAS mutational status (PANC1 - mutated KRAS and BxPC3 -; wild type KRAS), on BMJ exposure. Specifically, we employed Nuclear magnetic resonance (NMR) metabolomics and in vivo imaging platforms to assess whether BMJ modulates PanC cell metabolome, together with establishing the molecular metabolomic targets to better understand the relevance of altered metabolism in PanC management by BMJ. Multinuclear NMR metabolomics was performed post 72 hours of BMJ treatment followed by PLS-DA (partial least square discriminant analysis) assessments on the quantitative metabolic data sets to visualize the treatment group clustering; altered glucose uptake, lactate export and energy state were identified as the key components responsible for cell death induction. We next employed PANC1 xenograft model for assessing in vivo BMJ efficacy against PanC. Positron Emission Tomography ([18FDG]-PET) and Magnetic Resonance Imaging (MRI) on PANC1 tumor-bearing animals reiterated the in vitro results, with BMJ-associated significant changes in tumor volumes, tumor cellularity and glucose uptake. Additional studies in BMJ-treated PanC cells and xenografts displayed a strong decrease in the expression of glucose and lactate transporters GLUT1 and MCT4, respectively, supporting their role in metabolic changes by BMJ. Collectively, these results highlight BMJ-induced modification in PanC metabolomics phenotype and establish primarily lactate efflux and glucose metabolism, specifically GLUT1 and MCT4 transporters, as the potential metabolic targets underlying BMJ efficacy in PanC. Citation Format: Deepanshi Dhar, Rama Kant, Komal Raina, Michael F. Wempe, Natalie J. Serkova, Chapla Agarwal, Rajesh Agarwal. Modulation of glucose metabolism and lactate efflux in tumors by bitter melon juice in its efficacy against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5078.