Abstract B41: Metformin and indole-3-carbinol (I3C) modulate regulation of genes involved in dedifferentiation in chemo-resistant pancreatic cancer cells

Abstract

Abstract Pancreatic ductal adenocarcinoma remains one of the deadliest cancers and is projected to become the second leading cause of cancer death by 2020. More alarming, is the projection of death in minority populations for this cancer. Although several risk factors have been associated with the etiology of this cancer, such as smoking, diet, obesity and recently nicotine, it continues to steadily increase. Numerous studies have shown the importance of cancer stem cells in cancer resistance and self-renewal. Dedifferentiation of cancer cells requires key factors to be present in the tumor environment. These factors are regulated by key transcription factors that are known to control cancer stem cells and dedifferentiation. Using a human embryonic stem cell RT2 Profiler gene array, numerous stem cell genes expressed in pancreatic cancer cell lines (MIAPaca2, Panc1) can be identified. However, this study focused on those involved in dedifferentiation of cancer cells. Although both cell lines, Panc-1 and MIAPaCa2 (Mia), expressed high levels of SOX 2, NANOG, CD44, GATA 2, POU5F1 (OCT4), and other genes, differences were noted in the expression of GATA6. GATA6 is a zinc finger transcription factor that is known to play a role in regulating cellular differentiation and organogenesis in gut, lung and heart development and has been found to be overexpressed in pancreatic, gastric and esophageal cancers. A pathogenic gene signature has emerged for genes regulated by GATA6 that could provide potential drug targets. Mia cells, which are less resistance to the standard drug used for pancreatic cancer, gemcitabine, expressed higher levels of GATA6 compared to Panc1, a more resistance phenotype. Treatment of cells with I3C alone at 100 or 200 µM inhibited the expression of GATA6 in Mia cells, compared to Panc 1 cells. Treatment with metformin alone and in combination with I3C showed similar results. Modulation of other gene expressions was noted with treatment of I3C and metformin, such as DPPA2, THY1, CCNA2 and DPPA2. This study has shown that the dietary agent, I3C, alone and in combination with metformin down-regulate critical stem cell genes involved in dedifferentiation of cancer cells that should affect the maintenance of their pluripotency and self-renewal. Citation Format: Beverly Lyn-Cook, George Cooper, Beverly Word, George Hammons. Metformin and indole-3-carbinol (I3C) modulate regulation of genes involved in dedifferentiation in chemo-resistant pancreatic cancer cells. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B41.