title: HuR's role in gemcitabine efficacy: an exception or opportunity?
abstract: Over the next few years, research teams will focus on, and millions of dollars will be spent on, sorting through cancer genomes. Undoubtedly, 'druggable' targets and events will be discovered that will improve our understanding and, hopefully, treatment of cancer. Highlighting an alternative to this 'genome-centric' approach, this review will further explore an underappreciated mechanism of gene expression regulation, posttranscription mRNA:protein interactions. A key molecule involved in this mode of gene regulation is HuR and we have shown that HuR levels and HuR cellular distribution can predict how pancreatic cancer patients responded to the standard of care chemotherapy (i.e., gemcitabine). HuR regulates post-transcriptional processes through: (1) association with specific mRNA cargos with ARE-rich sequences and (2) stress-induced increased cytoplasmic protein levels. Over multiple laboratories and diverse tumor types, it has been shown that HuR supports tumor survival through its regulation of tumor-promoting transcripts such as VEGF. In this article, we will highlight a recent discovery that this potent post-transcriptional gene regulatory mechanism has an impact on a common chemotherapeutic, gemcitabine. Specifically, we have identified the mechanism by which HuR can regulate a key gemcitabine metabolic enzyme, deoxycytidine kinase. We will use this example to explore and hypothesize the functional roles that HuR may have on anticancer drug therapies. We will survey novel high throughput global gene expression analysis tools to discover novel HuR targets. Future multidisciplinary approaches focused on HuR biology will provide critical events and 'druggable' targets in cancer that large-scale genomic sequencing efforts will miss.
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. Jonathan.Brody@jefferson.edu
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Gonye
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D051959:ELAV Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine