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The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells

Oncogene volume 35, pages 2529–2541 (2016)Cite this article

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Abstract

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine–threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3′-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR’s regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

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Acknowledgements

We acknowledge the TJU’s Bioimaging core for their assistance with confocal image acquisition and analysis. We also acknowledge Zachary Schoepflin at the TJU Department of Orthopedic Surgery for his assistance with hypoxia chambers. This work was supported by NIH-NIGMS T32 GM008562 20 (to FFB), NIH-NCI R21 CA182692 01A1 (to JRB), American Cancer Society MRSG-14-019-01-CDD (to JMW), the Mary Halinski Pancreatic Cancer Research Fund (to JRB) and the Hirshberg Foundation (to JRB, JW).

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA

    F F Blanco

  2. Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA

    F F Blanco, M Jimbo, L Enyenihi, C J Yeo, J M Winter & J R Brody

  3. Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, VA, USA

    J Wulfkuhle, I Gallagher, J Deng & E Petricoin

  4. Novartis Institutes for Biomedical Research, Novartis, Switzerland

    N Meisner-Kober

  5. Center for Computational Medicine, Thomas Jefferson University, Philadelphia, PA, USA

    E Londin & I Rigoutsos

  6. Lankenau Institute for Medical Research, Philadelphia, PA, USA

    J A Sawicki

  7. Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA

    M V Risbud

  8. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    A K Witkiewicz

  9. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    P A McCue & W Jiang

  10. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    H Rui

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Blanco, F., Jimbo, M., Wulfkuhle, J. et al. The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells. Oncogene 35, 2529–2541 (2016). https://doi.org/10.1038/onc.2015.325

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