HuR Contributes to the Therapeutic Resistance of Pancreatic Cancer

Carmella Romeo Smith, Thomas Jefferson University


Pancreatic ductal adenocarcinoma (PDA) will soon be the 2nd leading cause of cancer-related death in the United States. Current treatments for newly diagnosed PDA generally exhibit a dismal 6 months survival rate, and although recent phase III clinical trials have increased the mean survival rate up to 1-year, these meager statistics establish a need for new or improved therapies. In order to improve upon established therapies for PDA, one must understand and overcome welldocumented therapeutic resistance. Post-transcriptional gene regulation (PTGR) has become an area of interest to account for acute drug resistance and cancer cell survival. PTGR is the rapid modulation of gene expression at the messenger RNA level, mostly involving regulation by microRNAs (miRNA) and/or RNA binding proteins (RBPs). Human antigen R (HuR), the most widely studied RBP, is predominately located in the nucleus, but upon tumor-associated stress, such as hypoxia or stress caused by treatment, translocates to the cytoplasm. The main role of cytoplasmic HuR is to stabilize target mRNA transcripts and positively or negatively regulate the expression of target genes, many of which are involved in cancer cell growth and survival. The current studies herein demonstrate two distinct roles for HuR in mediating drug resistance to Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) and gemcitabine, two well-established therapies for cancer. In the first chapter we demonstrate HuR associates with the mRNA of Death Receptor 4 (DR4), the primary death-inducing TRAIL receptor in PDA cells, resulting in downregulation of DR4 protein expression and resistance to TRAIL therapy. The second chapter builds upon our previously published studies, which demonstrated HuR positively regulates the protein expression of deoxycytidine kinase (dCK), a key enzyme in the gemcitabine (GEM) metabolism pathway. In the current study, siRNA silencing of Transportin-2 (TNPO2), the importin that is responsible for import of HuR protein into the nucleus, results in HuR remaining in the cytoplasm, hence up regulating dCK and rendering PDA cells more sensitive to GEM. We also show that TNPO2 mRNA is a novel HuR target, suggesting a role for HuR in regulating its own subcellular location. Taken together, these two chapters implicate HuR as a key regulator of therapy resistance in cancer cells and indicate a need for HuR-specific therapies in combination with other cancer therapies.

Subject Area

Molecular biology|Cellular biology

Recommended Citation

Smith, Carmella Romeo, "HuR Contributes to the Therapeutic Resistance of Pancreatic Cancer" (2016). ProQuest ETD Collection - Thomas Jefferson University. AAI10124160.