288 - Dissecting the Role of the Iron-Regulated Metastasis Suppressor NDRG1 in Regulating Endoplasmic Reticulum Stress and Cancer Cell Survival

Abstract

The iron-regulated stress response gene, N-myc downstream regulated gene 1 (NDRG1), functions as a metastasis suppressor in multiple cancer types. Importantly, NDRG1 expression is negatively correlated with tumour progression in pancreatic cancer. Interestingly, NDRG1 is regulated by multiple stressors, including hypoxia, oxidative stress and iron chelation. Recent studies have demonstrated that NDRG1 is able to influence the endoplasmic reticulum (ER) stress response. Consequently, studies were performed to assess the mechanisms underlying the association of NDRG1 and the ER stress response in human PANC1 pancreatic cancer cells. As part of these studies, anti-cancer redox active thiosemicarbazones (e.g., Dp44mT) were also examined as stressors that induce iron deprivation and redox stress to upregulate NDRG1. This class of agents is currently being assessed in clinical trials for the treatment of advanced solid tumors (NCT02688101). PANC1 NDRG1-overexpressing cells were shown to effect the three main arms of the ER stress response by: (1) increasing the cleavage of ATF6; (2) suppressing the PERK pathway; and (3) inhibiting the IRE1α arm, relative to PANC1 vector control cells. Additionally, NDRG1 overexpression was shown to increase the expression of the ER chaperones, BiP and calreticulin, while the chaperone, calnexin, remained unaltered. NDRG1 was also shown to form a complex with BiP through immunoprecipitation studies. Interestingly, Dp44mT was shown to increase NDRG1 expression and induce the phosphorylation and activation of IRE1α, ATF6 and PERK. Collectively, this investigation elucidated the underlying molecular mechanisms through which NDRG1 manipulates the ER stress response pathways and potentially re-sensitise pancreatic cancer cells to ER-induced apoptosis. These studies have provided valuable insights, which may ultimately aid the development of novel redox active anti-cancer agents capable of manipulating the metastasis suppressor NDRG1 and the ER stress response to induce cancer cell death.