Abstract 6071: Role of nitric oxide in the invasive pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is a metastatic tumor with an extremely low 5-year survival rate. Metastasis is a main cause of patient mortality as it is extremely difficult to treat. Thus, understanding the characteristics of cancer cell populations exhibiting the invasive phenotype is fundamental for developing novel strategies to counter metastasis and improve therapeutic efficacy. To characterize these invasive phenotypes, we compared the human PANC-1 parent cell line with PANC-1 cells (INV) that invaded through transwell inserts. INV cells exhibited increased invasiveness and higher resistance to Carbon-ion radiation compared to whole cultured, control PANC-1 cells (WCC). PANC-1 invasion was reduced by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. Cell invasion through extracellular membrane (ECM) involves complex regulation of cell adhesion and de-adhesion to ECM proteins. Suspended INV cells, as well as INV cells undergoing de-adhesion, showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, L-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and hampered spheroid formation ability, suggesting that NO can potentially influence PANC-1 aggressiveness. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK-independent mechanism promoted NOS/NO modulation of PANC-1 invasion. Furthermore, xenograft studies with INV and WCC in an NSG mouse model revealed a higher ability of INV in liver metastasis than WCC, and L-NAME diminished the metastasis observed in INV injected mice. In summary, these results implicate NO as a key mediator of therapeutic resistance to Carbon-ion radiation and metastasis of PANC-1 cells; inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells. Citation Format: Mayumi Fujita, Veena Somasundaram, Debashree Basudhar Basudhar, Robert Y.s. Cheng, Lisa A. Ridnour, Kaori Imadome, Jae Hong No, Gaurav Bharadwaj, David A. Wink. Role of nitric oxide in the invasive pancreatic cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6071.