Details

Autor(en) / Beteiligte

• Li, Ming-Yue
• Ding, Jie-Qiong
• Tang, Qiong
• Hao, Miao-Miao
• Wang, Bang-Hua
• Wu, Ji
• Yu, Liang-Zhu
• Jiao, Ming
• Luo, Bin-Hua
• Xie, Min
• Zhu, Hai-Li

Titel

SIRT1 activation by SRT1720 attenuates bone cancer pain via preventing Drp1-mediated mitochondrial fission

Ist Teil von

• Biochimica et biophysica acta. Molecular basis of disease, 2019-03, Vol.1865 (3), p.587-598

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Bone cancer pain (BCP) is the pain induced by primary bone cancer or tumor metastasis. Increasing evidence and our previous studies have shown that mammalian silent information regulator 2 homolog (SIRT1) is involved in periphery sensitization and central sensitization of BCP, and the underlying mechanism of SIRT1 in bone cancer pain may provide clues for pain treatment. Dynamin-related protein 1 (Drp1) is an essential regulator for mitochondrial fission. In this research, BCP model rats were established by injecting MRMT-1 rat mammary gland carcinoma cells into the left tibia of female Sprague-Dawley rats and validated by tibia radiographs, histological examination and mechanical pain test. As a result BCP rats exhibited bone destruction and sensitivity mechanical pain. BCP increased inflammatory cells infiltration and apoptosis, reduced SIRT1 protein expression and phosphorylation, and elevated Drp1 expression in spinal cord. An agonist of SIRT1 named SRT1720 intrathecal treatment in BCP rats increased SIRT1 phosphorylation, reduced the up-regulated Drp1 expression, and reversed pain behavior. SRT1720 also regulated Bcl-2/BAX and cleaved caspase-3 expressions, and inhibited mitochondrial apoptosis in spinal cord of BCP rats. For in vitro research, SRT1720 treatment decreased Drp1 expression in a dose-dependent manner, blocked CCCP-induced mitochondrial membrane potential change, consequently reduced apoptosis and promoted proliferation. These data suggest that SIRT1 activation by SRT1720 attenuated bone cancer pain via preventing Drp1-mediated mitochondrial fission. Our results provide new targets for therapeutics of bone cancer pain. •SRT1720 reduces BCP-induced apoptotic signal in spinal cord.•SRT1720 reverses the inhibitory effect of BCP on SIRT1 activity.•SIRT1 activation reduces pain behavior in BCP rats.•SRT1720 down-regulates Drp1 expression in spinal cord of BCP rats.•SRT1720 inhibits CCCP-induced mitochondrial membrane potential decrease in cells.