Metastasis-associated gene 1 (MTA1) enhances cisplatin resistance of malignant pleural mesothelioma by ATR-Chk1-mediated DNA repair

Our plain-English summary of Metastasis-associated gene 1 (MTA1) enhances cisplatin resistance of malignant pleural mesothelioma by ATR-Chk1-mediated DNA repair, by C. Xu, Y. Hu, B. Chen, et al (Annals of Translational Medicine, 2021).

The study

• Authors: C. Xu, Y. Hu, B. Chen, D. Li, R. Liang, M. Shen, M. Wu, M. Tao
• Journal: Annals of Translational Medicine
• Published: 2021;9(8):670
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) chemoresistance remains a challenge to oncologists. In our previous study, we demonstrated that the aberrant expression of metastasis-associated gene 1 (MTA1) is associated with carcinogenesis and metastasis in MPM. The aim of the present study was to investigate the mechanism of MTA1 and chemo-resistance in MPM.

Methods: Western blotting and real-time polymerase chain reaction were used to analyze the protein and mRNA levels. A stable clone with a knockdown of MTA1 was generated with shRNA via lentivirus technology in MPM cell lines. Cell Counting Kit-8 assay and crystal violet assay were used to measure cell viability. Immunochemical staining was employed to detect MTA1 expression in MPM tissues. The cell cycle of MPM cells was determined by phosphohistone H3 staining and flow cytometric analysis.

Results: The MTA1 protein was upregulated and enhanced cisplatin resistance in MPM. Cisplatin stabilized the expression of the MTA1 protein by inhibiting its ubiquitination, and MTA1 enhanced G2/M cell cycle delay and regulated and protected the tumor genome from chemotherapeutic drugs via participating in the phosphorylation of the ataxia telangiectasia mutated and rad3 related-checkpoint kinase 1 (ATR-Chk1) pathway.

Conclusions: These data suggest that MTA1 enhances cisplatin resistance by ATR-Chk1-mediated DNA damage repairment and cisplatin stabilizes MTA1 expression via affecting on the ubiquitination pathway of MTA1 in MPM. Our findings indicate that MTA1 could serve as a novel therapeutic target to overcome chemoresistance in MPM.

2021 Annals of Translational Medicine. All rights reserved.

In plain English

This laboratory study, which did not concern asbestos exposure, examined how a protein called MTA1 relates to cisplatin resistance in malignant pleural mesothelioma (MPM). The authors used two MPM cell lines, cisplatin-resistant versions of them, and tumor tissue from MPM patients. In 9 patients who developed cisplatin resistance, MTA1 protein increased after resistance, while MTA1 mRNA did not change. Among 30 patients grouped by MTA1 level (18 high, 12 low), those with high MTA1 had significantly shorter progression-free survival after cisplatin-based chemotherapy. In cells, lowering MTA1 made them more sensitive to cisplatin, with IC50 values changing 1.7- to 1.9-fold. The IC50 is the cisplatin concentration that cut measured cell viability in half. Cisplatin reduced the attachment of a small protein, ubiquitin, to MTA1, which the authors concluded helps, at least in part, to stabilize MTA1 protein. Lowering MTA1 weakened the cisplatin-induced cell-cycle delay at the G2/M stage and reduced activation of the ATR-Chk1 DNA damage pathway. The authors concluded that their data suggest MTA1 enhances cisplatin resistance through ATR-Chk1-mediated DNA repair and could serve as a therapeutic target. They noted that compelling evidence on the clinical efficacy of MTA1 inhibitors is still lacking.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of human MPM cell lines, with analysis of MPM patient tissue samples
• Who was studied: MPM cell lines MSTO-211H and NCI-H2452 (with cisplatin-resistant subclones MSTO-DDP and H2452-DDP), plus tissue from MPM patients at the First Affiliated Hospital of Soochow University, China. The Methods say 39 patients. The Results use 9 patients who developed cisplatin resistance, 2 patients for immunohistochemistry, and 30 patients grouped by MTA1 level (12 low, 18 high).
• Exposure: No asbestos exposure was studied. The exposure was the chemotherapy drug cisplatin, applied to cells (including step-wise increasing concentrations over 15 months to create resistant lines) and given to patients as cisplatin-based chemotherapy. MTA1 levels were also lowered experimentally (shRNA, siMTA1).
• Main results:
  • In 9 MPM patients who developed cisplatin resistance, MTA1 protein increased significantly after resistance, while MTA1 mRNA did not change.
  • Among 30 patients grouped by MTA1 level, those with high MTA1 protein had significantly shorter progression-free survival after cisplatin-based chemotherapy than those with low MTA1.
  • Cisplatin IC50 values differed 1.9-fold (H2452) and 1.8-fold (MSTO) between ordinary cells and MTA1-knockdown cells. The figure table indicates lower IC50 values in the knockdown cells.
  • Cisplatin-resistant cell lines had significantly more MTA1 protein than the original lines. Lowering MTA1 with siMTA1 reduced cisplatin IC50 values 1.8-fold (H2452-DDP) and 1.7-fold (MSTO-DDP).
  • In MPM cells, cisplatin raised MTA1 protein (peaking at 48 h) without changing MTA1 mRNA, and significantly reduced ubiquitination (attachment of ubiquitin) of MTA1. The authors concluded that this promotes MTA1 protein stability, at least in part.
  • Cisplatin arrested H2452 cells in the G2/M phase, and knocking down MTA1 attenuated this effect. The same result was seen in MSTO cells.
  • In MTA1-knockdown cells treated with cisplatin, p-ATR, p-Chk1, Chk1 and Claspin were significantly reduced. MTA1 bound to ATR in a way the authors found to be independent of DNA.
• The authors' conclusion: The authors concluded that their data suggest three things: MTA1 enhances cisplatin resistance in MPM through ATR-Chk1-mediated DNA damage repair; cisplatin stabilizes MTA1 by affecting its ubiquitination; and MTA1 could serve as a novel therapeutic target to overcome chemoresistance.
• Limitations the authors state:
  • The authors state that compelling evidence on the clinical efficacy of MTA1 inhibitors is still lacking and that further studies are warranted.

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Cisplatin, Pleural Mesothelioma, Carcinogenesis.

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