Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

Abstract

Background Thyroid cancer (TC) is the most common type of endocrine malignancy and its incidence is increasing over years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve the significant effects of it due to aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), and these are regarded as the most malignant types of TC. Glucose-regulated protein (GRP78) is the key molecule of tumor growth, apoptosis and metastasis. However, the underlying mechanisms of GRP78 in TC still require discussion. This study aimed to explore the role of GRP78 and its potential mechanism in TC. Results GRP78 expression was increased in TC tissues when compared with adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative ability of ATC cells in in vitro studies. In addition, tunicamycin-induced ER stress up-regulated the expression of GRP78, PERK and XBP1 as well as reversed the metastatic ability of GRP78 in ATC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-sequencing data with regard to si-GRP78 and si-control showed that GRP78 might regulate the ability of metastasis through extracellular matrix (ECM) remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13, which were highly relevant to ATC cells. The analysis of GEPIA database confirmed that high genomic amplification of MMP13 and COL1A1 in TC tissues showed correlation with TNM stage. Further western blotting analysis showed that MMP13 might be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 that is suppressed by GRP78 depletion. Conclusions GRP78 acts as an important regulator of metastasis under ER stress. In addition, the function of GRP78 might be mediated by ECM remodeling in ATC cells, implicating it as a therapeutic target in TC.

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis

“…Endoplasmic reticulum (ER) facilitates the processing of newly formed prosurvival and proproliferation proteins required for tumor growth and metastasis. Impaired ER activity or ER stress has been shown to contribute to thyroid carcinoma metastasis [ 5 , 6 ]. Another study reported that ER stress reduced the radiosensitivity of thyroid carcinoma cells and inhibited apoptosis [ 7 , 8 ].…”

Structure-Based Insight on the Mechanism of N-Glycosylation Inhibition by Tunicamycin

“…In addition to antibiotics, several studies have revealed that tunicamycin has anticancer effects ( Wang et al, 2020 ; Wu et al, 2018 ; Zhao et al, 2020 ). It was confirmed that tunicamycin showed anticancer effects in various cancers such as gastric cancer as well as head and neck cancer.…”

“…It was confirmed that tunicamycin showed anticancer effects in various cancers such as gastric cancer as well as head and neck cancer. Tunicamycin induces strong ER stress and exhibits anticancer effects because it effectively blocks N-glycosylation in cancer cells ( Wang et al, 2020 ; Wu et al, 2018 ; Zhao et al, 2020 ). Hence, while it is currently difficult to use tunicamycin as an anticancer agent due to its toxicity, the possibility of its development as a new anticancer agent is substantial, as it has shown to have strong anticancer potential.…”

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology

“…MMP-9 in turn enhances cell invasion and metastasis by digesting ECM and intercellular adhesion proteins [ 113 , 127 ]. Furthermore, XBP1-s can directly regulate ECM remodeling and promote thyroid cancer metastasis [ 128 ].…”