5‐Fluorouracil and Gemcitabine Alter Nuclear Transport

Abstract

The GTPase, Ran, is a major regulator of nuclear transport and disruption of its established gradient disrupts nuclear export and leads to cell death through the accumulation of pro‐apoptotic factors. The chemotherapy 5‐Fluorouracil (5‐FU) increases nuclear pore permeability causing Ran to leak into the cytoplasm, disrupting the gradient and in turn nuclear export, leading to cell death of HeLa cervical cancer cells. Our previous work demonstrated that combining 5‐FU with topoisomerase inhibitors can have a greater total impact on disruption of the Ran gradient and accumulates proteins in the nucleus. Gemcitabine (GEM) is widely used when treating pancreatic cancer; yet a resistance is common. However, combination of GEM with nuclear export inhibitors can help overcome this problem. Therefore, we sought to determine if combination of 5‐FU and GEM could impact nuclear export to help overcome GEM resistance. Our initial studies found that 5‐FU+GEM further decreased nuclear Ran in HeLa cells and lead to increased cell death in combination over GEM alone. Therefore, we transitioned to exploring the effects of 5‐FU+GEM on disrupting the Ran gradient in PANC1 pancreatic cells. Both 5‐FU and GEM individually and in combination decreased the nuclear Ran levels by 15%, 17%, and 23% respectively. This disruption of nuclear export may help overcome GEM resistance in PANC1 cells. Specifically, our ongoing work is exploring the impact of 5FU+GEM on the nuclear retention of the tumor suppressors p27 and p21 as well as cell viability to identify a possible mechanism for the impact of the 5‐FU+GEM combination on apoptosis. Our work helps support a possible mechanism for overcoming GEM resistance in Panc1 cells and identifies a potential combination treatment with 5‐FU for use against pancreatic cancer.