Abstract 1889: Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer
Authors: Rajasekaran Devaraja , Ogura Jiro , Wachtel Mitchell , Ramachandran Sabarish , Babu Ellappan , Sivaprakasam Sathish , Grippo Paul J. , Torres Carolina , Muthusamy Thangaraju , Gnana-Prakasam Jaya P. , Bhutia Yangzom D. 
Published: August 2019

Pancreatic cancer especially the pancreatic ductal adenocarcinoma (PDAC) is by far the most lethal of all cancers with a five year survival rate of less than 5%. Gemcitabine is currently used as a first line therapy for locally advanced and metastatic PDAC but with a very low success rate. Hence, there is an urgent need to better understand what actually drives this cancer so as to come up with a better diagnostic and therapeutic strategies. Excess heme and iron are known to be pro-tumorigenic. When present in excess, these molecules become toxic. Fe2+ in free form is a potent oxidant; it catalyzes the Fenton reaction to generate hydroxyl radicals (Fe2++ H2O2 → Fe3+ + HO• + OH-), a potent reactive oxygen species. Free heme is also toxic as it catalyzes free radical reaction and induces oxidative damage. Accumulation of iron and heme to toxic levels occurs in genetic diseases (hemochromatosis, sickle cell disease), pathological conditions (hemolytic anemia, ischemia reperfusion), infections, and clinical/therapeutic conditions (repeated blood transfusion). Excess intake of iron and heme from dietary sources could also lead to iron/heme overload, particularly in the colon. In this regard, red meat with its ~10-fold higher heme content than white meat is specifically relevant. Among these conditions however, hemochromatosis deserves special mention. Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or epigenetic causes, predisposes an individual to cancer. We employed cell culture studies to interrogate the connection between excess iron and cancer in multiple tissues and combined in vitro and in vivo studies to explore the connection in pancreas further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition (EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity. In order to further extrapolate our cell culture data, we generated EL-KRASG12D or EL-Kras mouse (pancreatic neoplastic mouse model) expressing Hfe+/+ and Hfe-/- genetic background. p53 target gene expression decreased in EL-Kras/Hfe-/- mouse pancreas compared to EL-Kras/Hfe+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms (CPN) decreased in EL-Kras/Hfe-/- mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss within pancreatic epithelial cells.

Citation Format: Devaraja Rajasekaran, Jiro Ogura, Mitchell Wachtel, Sabarish Ramachandran, Ellappan Babu, Sathish Sivaprakasam, Paul J. Grippo, Carolina Torres, Thangaraju Muthusamy, Jaya P. Gnana-Prakasam, Yangzom D. Bhutia. Chronic exposure to excess iron promotes EMT and cancer via p53 loss in 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 1889.