Abstract A71: Post-transcriptional regulation of the proto-oncogene PIM1 by the mRNA stability factor HuR: implications for pancreatic cancer therapeutic response and cell survival

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by its insidious development and resistance to conventional and targeted therapies. As a result of selective pressures imposed by cytotoxic agents and the tumor microenvironment, PDA cells orchestrate a potent and elusive chemoresistant mechanism. Recently, the serine-threonine kinase PIM1 has emerged as a key regulator of PDA cell survival under cancer-associated stress (e.g: cytotoxic DNA-damaging agents, hypoxia). However, the molecular mechanism behind PIM1 overexpression in PDAs is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present in the PIM1 mRNA 3’UTR mediate a regulatory interaction with the mRNA-stability factor HuR under clinically relevant hypoxic and chemotherapeutic stress. Given the previously described role of HuR in PDA cell survival and therapeutic response, we sought to determine if HuR-mediated regulation of PIM1 is essential to promote cell survival and therapeutic resistance under tumor-associated stress (e.g.: hypoxia, chemotherapy). Accordingly, PDA cells subjected to hypoxia exhibit dramatic elevated expression of PIM1 mRNA and protein. Moreover, siRNA-mediated knockdown of HuR abrogates hypoxia-mediated induction of PIM1. HuR-mediated stabilization of PIM1 is associated with high HuR cytoplasmic expression. As revealed by immunofluorescence and western blot analyses of fractionated lysates, we demonstrate that HuR translocates to the cytoplasm...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Heterogeneity in Tumor Progression Source Type: research