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Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage

Cancer Gene Therapy volume 29, pages 1487–1501 (2022)Cite this article

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Abstract

DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu5) on chemosensitivity in HCC and chemotoxicity to the normal liver. The expression of mGlu5 was higher in HCC than in the normal liver, and correlated with poor prognosis according to The Cancer Genome Atlas database and Integrative Molecular Database of Hepatocellular Carcinoma. Cisplatin, oxaliplatin or methyl methanesulfonate (MMS) caused cell death by decreasing mGlu5 expression in HCC cells and increased mGlu5 expression in hepatic cells. In HCC cells, inhibition of mGlu5 aggravated MMS-induced DNA damage by increasing intracellular Ca2+ overload and mitogen-activated protein kinase (MAPK) activation, thereby promoting cell death, and activation of mGlu5 rescued the effect of MMS. However, in hepatic cells, mGlu5 inhibition alleviated MMS-induced DNA damage by downregulating Ca2+-derived MAPK pathways to advance hepatic cell survival. The opposite effects of mGlu5 overexpression or knockdown on MMS-induced DNA damage supported that cell death is a result of the differential regulation of mGlu5 expression. Inhibition of mGlu5 increased chemosensitivity and decreased chemotoxicity in a rat tumor model. This study suggests that mGlu5 inhibition could act synergistically with HCC chemotherapeutics with minimal side effects, which may improve the treatment of patients with HCC in the future.

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Fig. 1: mGlu5 differentially expresses in HCC and normal liver.
Fig. 2: Blocked mGlu5 increases chemosensitivity of cisplatin and oxaliplatin in HCC cells but resists chemotoxicity in hepatic cells.
Fig. 3: Blocked mGlu5 increases MMS-induced DNA damage via regulating [Ca2+]i and MAPK pathways in HCC cells.
Fig. 4: Blocked mGlu5 decreases MMS-induced DNA damage in hepatic cells.
Fig. 5: Blocked mGlu5 reduces MMS-induced DNA damage through [Ca2+]i and MAPK pathways.
Fig. 6: Alteration of mGlu5 expression reverses MMS-induced cytotoxicity in HCC cells and hepatic cells.
Fig. 7: Blocked mGlu5 enhances the chemosensitivity and relieves chemotoxicity in vivo.

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Data availability

The datasets and materials used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all members in the group for helpful suggestions. We thank International Science Editing (http://www.internationalscienceediting.com, quotation number ISE 86005) for editing this manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (81972231, 81372587, and 81171886).

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Authors and Affiliations

  1. Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China

    Hui-Min Yang, Tian-Zhong Hou, Ya-Nan Zhang, Shu-Dong Zhao & Hong Zhang

  2. Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, 100083, Beijing, China

    Shu-Dong Zhao

  3. Center of Hepatic and Digestive Disease, Beijing YouAn Hospital, Capital Medical University, 100069, Beijing, China

    Yong-Le Wu

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Contributions

HZ designed the research program and charged correspondence; HMY performed the most of experiments, analyzed the data and wrote the manuscript; TZH, YNZ and SDZ performed the part of experiments; YLW collected patient samples. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Hong Zhang.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the ethics committee of Capital Medical University (2019SY040). All experimental protocols involving animals were approved by the Committee on Animal Care and Usage of Capital Medical University (SCXK 2016-0006).

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Yang, HM., Hou, TZ., Zhang, YN. et al. Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage. Cancer Gene Ther 29, 1487–1501 (2022). https://doi.org/10.1038/s41417-022-00465-2

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