Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells.

Dmytro Starenki,Ricardo V Lloyd,Jong-In Park,Seung-Keun Hong,Nadiya Sosonkina

doi:10.3390/ijms20092069

Abstract

We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated in other thyroid tumor types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC), and that mortalin depletion can effectively induce growth arrest and cell death in human PTC (TPC-1), FTC (FTC133), and ATC (8505C and C643) cells in culture. Intriguingly, mortalin depletion induced varied effects on cell cycle arrest (G0/G1 phase arrest in TPC-1 and C643, G2/M phase arrest in 8505C, and mild G2/M phase arrest with increased sub-G0/G1 population in FTC133) and on the levels of TP53, E2F-1, p21CIP1, p27KIP1, and poly (ADP-ribose) polymerase cleavage in these cells, suggesting that thyroid tumor cells respond to mortalin depletion in a cell type-specific manner. In these cells, we also determined the efficacy of triphenyl-phosphonium-carboxy-proxyl (Mito-CP) because this mitochondria-targeted metabolism interfering agent exhibited similar tumor suppressive effects as mortalin depletion in MTC cells. Indeed, Mito-CP also induced robust caspase-dependent apoptosis in PTC and ATC cell lines in vitro, exhibiting IC50 lower than PLX4032 in 8505C cells and IC50 lower than vandetanib and cabozantinib in TPC-1 cells. Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer.

Highlights

Thyroid cancer, the most common neoplasm of the endocrine system, is the seventh most frequent human malignancy and its incidence is increasing more rapidly than any other cancers
Using a mortalin-specific antibody validated for IHC in our previous reports [12,13], we found that mortalin protein levels were significantly upregulated in papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC) but not in the benign tumor tissues (Figure 1A,B)
Targeted therapy using the small molecule inhibitors of oncogenic receptor tyrosine kinases or molecular switches has been significantly advanced in recent years for the treatment of surgically incurable progressive thyroid cancers, e.g., RET and VEGF inhibitors for medullary thyroid cancer (MTC), and B-Raf and MEK1/2 inhibitors for B-RafV600E PTC and ATC

Summary

Introduction

The most common neoplasm of the endocrine system, is the seventh most frequent human malignancy and its incidence is increasing more rapidly than any other cancers. Thyroid cancer is mainly treated by surgery and radioiodine remnant ablation but these therapies are effective only for non-metastasized primary tumors. Most of metastatic or relapsed thyroid tumors are incurable, demanding advanced therapeutic modalities for patient survival (reviewed in [1,2]). Depending upon the cell of origin and histological characteristics, thyroid carcinomas are generally classified as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma (ATC, undifferentiated), and medullary thyroid cancer (MTC). PTC, FTC, and ATC arise from the follicular thyrocytes whereas MTC is the only parafollicular C-cell-derived tumor, constituting the minor fraction of thyroid malignancies [1,2].

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