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Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells

Oncogene volume 34, pages 4624–4634 (2015)Cite this article

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Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. For therapy of advanced MTC, the Food and Drug Administration recently approved vandetanib and cabozantinib, the tyrosine kinase inhibitors targeting RET, vascular endothelial growth factor receptor, epidermal growth factor receptor and/or c-MET. Nevertheless, not all patients respond to these drugs, demanding additional therapeutic strategies. We found that mortalin (HSPA9/GRP75), a member of HSP70 family, is upregulated in human MTC tissues and that its depletion robustly induces cell death and growth arrest in MTC cell lines in culture and in mouse xenografts. These effects were accompanied by substantial downregulation of RET, induction of the tumor-suppressor TP53 and altered expression of cell cycle regulatory machinery and apoptosis markers, including E2F-1, p21CIP1, p27KIP1 and Bcl-2 family proteins. Our investigation of the molecular mechanisms underlying these effects revealed that mortalin depletion induces transient MEK/ERK (extracellular signal–regulated kinase) activation and altered mitochondrial bioenergetics in MTC cells, as indicated by depolarized mitochondrial membrane, decreased oxygen consumption and extracellular acidification and increased oxidative stress. Intriguingly, mortalin depletion induced growth arrest partly via the MEK/ERK pathway, whereas it induced cell death by causing mitochondrial dysfunction in a Bcl-2-dependent manner. However, TP53 was not necessary for these effects except for p21CIP1 induction. Moreover, mortalin depletion downregulated RET expression independently of MEK/ERK and TP53. These data demonstrate that mortalin is a key regulator of multiple signaling and metabolic pathways pivotal to MTC cell survival and proliferation, proposing mortalin as a novel therapeutic target for MTC.

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Acknowledgements

We thank Dr Sergey Tarima at the Division of Biostatistics, Medical College of Wisconsin (MCW) for statistical analysis; Dr Alexandra F Lerch-Gaggl (Pediatric BioBank and Analytical Tissue Core, MCW) for imaging immunohistochemistry data; and the MCW Cancer Center Bioenergetics shared resource and Advancing Healthier Wisconsin for Seahorse analysis. This work was supported by the American Cancer Society (RSGM-10-189-01-TBE) and the National Cancer Institute (R01CA138441) to J-IP.

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Authors and Affiliations

  1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

    D Starenki, S-K Hong & J-I Park

  2. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA

    R V Lloyd

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  1. D Starenki
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Correspondence to J-I Park.

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Starenki, D., Hong, SK., Lloyd, R. et al. Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 34, 4624–4634 (2015). https://doi.org/10.1038/onc.2014.392

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