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

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.