SIRT2 Prevents Cisplatin-Induced Neuron Injury By Promoting Nucleotide Excision Repair

Abstract

Radiation and chemotherapy-induced neuropathy are some of the most common causes of dose reduction and discontinuation of cancer treatment, and often cause a major permanent impairment of quality of life in cancer patients. Furthermore, chemotherapy-induced neuropathy acts as a risk factor for development of radiation-induced neuropathy in patients receiving concomitant or adjuvant radiotherapy. The lack of effective treatments for or prevention of this debilitating neuronal toxicity not only compromises optimal treatment, but also leaves cancer survivors with significant disability. Here, we sought to investigate the biological role and underline molecular mechanisms of sirtuin 2 (SIRT2) in cisplatin neurotoxicity. Genetic murine models were utilized to compare the development of cisplatin-induced peripheral neuropathy in transgenic Sirt2 knock-in (Sirt2-KI) mice versus wild-type (WT) mice. The hyperalgesia seen in neuropathy was measured in terms of mechanical and thermal thresholds. Immunostaining and western blot were used to monitor SIRT2 expression in dorsal root ganglion (DRG) sensory neurons. The efficiency of DNA damage repair via nucleotide excision repair (NER) was examined using a dual-luciferase reporter assay, while neuronal cytotoxicity was determined using a trypan blue staining assay. In addition to the genetic approach, the function of SIRT2, an NAD+deacetylase, was pharmacologically modified to validate its role in prevention and treatment of cisplatin-induced neuropathy. High expression of SIRT2 in Sirt2-KI mice produces significant resistance to cisplatin-induced neuropathy compared to WT mice. Cisplatin provoked a nuclear translocation of SIRT2 in DRG sensory neurons, protecting mice against neuropathy. Overexpression of SIRT2 resulted in significantly improved cultured neuronal cell survival through the promotion of nucleotide excision repair of cisplatin-induced DNA crosslinks. In vivo inhibition of NER abolished SIRT2-mediated neuroprotection as evidenced by reductions in mechanical and thermal hyperalgesia thresholds. Finally, administration of nicotinamide riboside activated SIRT2 and prevented cisplatin-induced neuropathy. SIRT2 prevents cisplatin-induced neuron injury by regulating the NER pathway. Identification of this novel function warrants future investigation of nicotinamide riboside-mediated neuroprotection during platinum-based cancer treatment.