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 2

Cisplatin induces SIRT2 nuclear accumulation.

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Cisplatin induces SIRT2 nuclear accumulation. (A) Representative images ...
(A) Representative images (original magnification, ×400) of immunofluorescence-stained SIRT2 and (B) quantification of nuclear SIRT2 in neuronally differentiated 50B11 cells treated with saline or 16 hours of cisplatin (n = 3). (C) Nuclear and cytoplasmic fractionated Western blot demonstrating that cisplatin increased nuclear accumulation of SIRT2 in 50B11 cells (n = 2). Histone H1 and α-tubulin served as the nuclear and cytoplasmic protein loading controls, respectively. Relative nuclear SIRT2 represents band intensity of nuclear SIRT2 normalized to the corresponding histone H1 relative to nuclear SIRT2 intensity without treatment. (D) Representative images (×630) of immunofluorescence-stained paraffin sections of DRGs from saline-treated and cisplatin-treated C57BL/6 mice 48 hours after treatment. An anti-SIRT2 antibody was used to visualize SIRT2, and arrows indicate neurons with nuclear SIRT2. (E) Dynamic distribution of neurons with nuclear SIRT2 during a 7-day period after cisplatin (n = 9). Images represent 1 of 3 replicates. Statistical significance was assessed using a 2-tailed Student’s t test with Welch’s correction (B) or 1–way ANOVA with Dunnett’s correction (E). **P < 0.01; ***P < 0.001.