Faculty Collaboration Database

Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 2015 Aug 27;34(35):4624-34

Date

12/02/2014

Pubmed ID

25435367

Pubmed Central ID

PMC4451452

DOI

10.1038/onc.2014.392

Scopus ID

2-s2.0-84940580797 (requires institutional sign-in at Scopus site)   63 Citations

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, p21(CIP1), p27(KIP1) 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 p21(CIP1) 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.

Author List

Starenki D, Hong SK, Lloyd RV, Park JI

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Carcinoma, Medullary
Carcinoma, Neuroendocrine
Cell Line, Tumor
Cell Proliferation
Cell Survival
Female
HSP70 Heat-Shock Proteins
Humans
MAP Kinase Signaling System
Mice, Nude
Mitochondrial Proteins
Neoplasm Transplantation
Oxidative Stress
Proto-Oncogene Proteins c-bcl-2
Resting Phase, Cell Cycle
Thyroid Neoplasms
Transcriptional Activation
Tumor Suppressor Protein p53
Up-Regulation