SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair
Manchao Zhang, … , Shengkai Jin, Fen Xia
Manchao Zhang, … , Shengkai Jin, Fen Xia
Published March 5, 2020
Citation Information: J Clin Invest. 2020;130(6):2953-2965. https://doi.org/10.1172/JCI123159.
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Research Article Neuroscience Oncology

SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair

Abstract

Platinum-based chemotherapy–induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA cross-links. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2’s protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2’s function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation–mediated neuroprotection during platinum-based cancer treatment.

Authors

Manchao Zhang, Wuying Du, Scarlett Acklin, Shengkai Jin, Fen Xia

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Figure 7

SIRT2’s protection of mice from CIPN is dependent on NER function.

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SIRT2’s protection of mice from CIPN is dependent on NER function. (A) C...
(A) Cisplatin and spironolactone (SP) treatment regimen for both Sirt2-KI and Sirt2-KO mice. Both strains of mice received the same treatments: saline, cisplatin alone, SP alone, or both cisplatin and SP. Response of (B) Sirt2-KI mice and (D) Sirt2-KO mice to mechanical stimulation, as measured by von Frey tests, is shown as relative paw-withdrawal threshold (RPWT). Response of the same Sirt2-KI mice (C) and Sirt2-KO mice (E) to thermal stimulation, as measured by hot plate tests, is shown as relative hot plate latency (RHPL). Varying sample sizes were due to the death of some mice from treatment toxicity. Statistical significance was assessed using 1-way ANOVA with Dunnett’s correction (B–E). *P < 0.05; **P < 0.01; ***P < 0.001.