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.
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.
Cancer Gene Ther. 2022 Oct;29(10):1487-1501. doi: 10.1038/s41417-022-00465-2. Epub 2022 Apr 8.
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 (mGlu) on chemosensitivity in HCC and chemotoxicity to the normal liver. The expression of mGlu 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 mGlu expression in HCC cells and increased mGlu expression in hepatic cells. In HCC cells, inhibition of mGlu aggravated MMS-induced DNA damage by increasing intracellular Ca overload and mitogen-activated protein kinase (MAPK) activation, thereby promoting cell death, and activation of mGlu rescued the effect of MMS. However, in hepatic cells, mGlu inhibition alleviated MMS-induced DNA damage by downregulating Ca-derived MAPK pathways to advance hepatic cell survival. The opposite effects of mGlu overexpression or knockdown on MMS-induced DNA damage supported that cell death is a result of the differential regulation of mGlu expression. Inhibition of mGlu increased chemosensitivity and decreased chemotoxicity in a rat tumor model. This study suggests that mGlu inhibition could act synergistically with HCC chemotherapeutics with minimal side effects, which may improve the treatment of patients with HCC in the future.
DNA 损伤剂被用作许多癌症的化疗药物，包括肝细胞癌 (HCC)。然而，它们与化疗敏感性低和肝损伤诱导等问题相关，这凸显了需要寻找新的治疗方法。在这里，我们研究了代谢型谷氨酸受体 5 (mGlu) 对 HCC 化疗敏感性和正常肝脏化疗毒性的差异调节作用。mGlu 在 HCC 中的表达高于正常肝脏，并且根据癌症基因组图谱数据库和肝细胞癌综合分子数据库与预后不良相关。顺铂、奥沙利铂或甲磺酸甲酯 (MMS) 通过降低 HCC 细胞中的 mGlu 表达和增加肝细胞中的 mGlu 表达导致细胞死亡。在 HCC 细胞中，mGlu 抑制通过增加细胞内 Ca 超载和丝裂原活化蛋白激酶 (MAPK) 激活来加重 MMS 诱导的 DNA 损伤，从而促进细胞死亡，而 mGlu 的激活则挽救了 MMS 的作用。然而，在肝细胞中，mGlu 抑制通过下调 Ca 衍生的 MAPK 途径减轻 MMS 诱导的 DNA 损伤，从而促进肝细胞存活。mGlu 过表达或敲低对 MMS 诱导的 DNA 损伤的相反影响表明，细胞死亡是 mGlu 表达差异调节的结果。mGlu 抑制在大鼠肿瘤模型中增加了化疗敏感性并降低了化疗毒性。这项研究表明，mGlu 抑制可能与 HCC 化疗药物协同作用，副作用最小，这可能会改善未来 HCC 患者的治疗效果。
