Nuclear Receptor Coactivator 3 in Endoplasmic Reticulum Stress and Stress Granule Dynamics in Pancreatic Cancer

Pancreatic cancer is predicted to be the second-leading cause of cancer-related deaths within the next decade. Nuclear receptor coactivator 3 (NCOA3/SRC3/AIB1) regulates an array of metabolic and signaling pathways and has been established by our group and others as a critical regulator pancreatic cancer progression and metastasis. A recent study demonstrated NCOA3 regulation by the IRE1α-XBP1 axis of the unfolded protein response (UPR), suggesting a link between NCOA3 and cellular stress management. Furthermore, NCOA3 has been shown to directly bind to a scaffolding protein of stress granules (SGs). Since SG assembly is regulated by the UPR, we hypothesized that NCOA3 in pancreatic cancer cells plays an important a role in mediating the endoplasmic reticulum (ER) stress response by modulating the dynamics of stress granules. Analysis of The Cancer Genome Atlas dataset illustrated a significant inverse correlation between NCOA3 expression and overall patient survival. The in vitro microarray and cytotoxicity experiments demonstrated a link between NCOA3 expression and (ER) stress tolerance. Induction of SGs in COLO 357 cells demonstrated a time-dependent colocalization of NCOA3 with SGs, and immunoprecipitation experiments indicated its localization within the shell of SG architecture. Silencing of NCOA3 using shRNA induced significant changes in SG dynamics while inhibition using pharmacological inhibitors showed mixed effects. Additionally, reduced NCOA3 expression resulted in changes in expression and phosphorylation of UPR proteins. Together, this study suggests a relationship between NCOA3 expression and ER stress tolerance, with NCOA3 displaying dual roles both as a coactivator of gene expression and client protein of SGs