☆ 4.7 Article

Absence of MGST1 mRNA and protein expression in human neuroblastoma cell lines and primary tissue

FREE RADICAL BIOLOGY AND MEDICINE (2014)

Journal

FREE RADICAL BIOLOGY AND MEDICINE

Volume 69, Issue -, Pages 167-171

Publisher

ELSEVIER SCIENCE INC

DOI: 10.1016/j.freeradbiomed.2014.01.021

Keywords

MAPEG; Microsomal glutathione transferase; MGST1; MGST2; MGST3; Neuroblastoma; Oxidative stress; Free radicals

Funding

National Institutes of Health Award [1R01ES013687]
FDA Award [FD-R-002319S1]
Swedish Research Council, Swedish Foundation for Strategic Research, VINNOVA
Karolinska Institutet

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Abstract

A recent study identified a haplotype on a small region of chromosome 12, between markers D12S1725 and D12S1596, shared by all patients with familial neuroblastoma (NB). We previously localized the human MGST1 gene, whose gene product protects against oxidative stress, to this very same chromosomal region (12p112.1-p13.33). Owing to the chromosomal location of MGST1; its roles in tumorigenesis, drug resistance, and oxidative stress; and the known sensitivity of NB cell lines to oxidative stress, we considered a role for MGST1 in NB development. Surprisingly there was no detectable MGST1 mRNA or protein in either NB cell lines or NB primary tumor tissue, although all other human tissues, cell lines, and primary tumor tissue examined to date express MGST1 at high levels. The mechanism behind the failure of NB cells and tissue to express MGST1 mRNA is unknown and involves the failure of MGST1 pre-mRNA expression, but does not involve chromosomal rearrangement or nucleotide variation in the promoter, exons, or 3' untranslated region of MGST1. MGST1 provides significant protection against oxidative stress and constitutes 4 to 6% of all protein in the outer membrane of the mitochondria. As NB cells are extremely sensitive to oxidative stress, and often used as a model system to investigate mitochondrial response to endogenous and exogenous stress, these findings may be due to the lack of expression MGST1 protein in NB. The significance of this finding to the development of neuroblastoma (familial or otherwise), however, is unknown and may even be incidental. Although our studies provide a molecular basis for previous work on the sensitivity of NB cells to oxidative stress, and possibly marked variations in NB mitochondrial homeostasis, they also imply that the results of these earlier studies using NB cells are not transferable to other tumor and cell types that express MGST1 at high concentrations. (C) 2014 Elsevier Inc. All rights reserved.

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Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma

Jie Zhang, Zhi-wei Ye, Paramita Chakraborty, Zhenwu Luo, John Culpepper, Muhammad Aslam, Leilei Zhang, Katarina Johansson, Jesper Z. Haeggstrom, Jianqiang Xu, Magnus Olsson, Danyelle M. Townsend, Shikhar Mehrotra, Ralf Morgenstern, Kenneth D. Tew

Summary: In this study, the researchers found that MGST1 is highly expressed in malignant and drug-resistant melanomas, and it specifically affects metastatic spread and therapeutic sensitivity. Loss of MGST1 increases cellular oxidative stress, decreases energy metabolism pathways, and enhances sensitivity to anticancer drugs and ferroptotic cell death. Targeting MGST1 can alter the redox balance, limit metastases in melanoma, and enhance the therapeutic index for chemo- and immunotherapies.

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