Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein,we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3′-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR’s role in affecting TRAIL apoptotic-resistance. NanoString{trade mark, serif} analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in anti-apoptotic processes. Taken together, these data extend HuR’s role as a key regulator of TRAIL-induced apoptosis.
Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAILPage-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).
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