Cisplatin triggers oxidative stress, apoptosis and pro-inflammatory responses by inhibiting the SIRT1-mediated Nrf2 pathway in chondrocytes

Pei Ling Hsieh, Kun Ling Tsai, Wan Ching Chou, Chin Hsien Wu, I. Ming Jou, Yuan Kun Tu, Ching Hou Ma

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Although the height of the proliferating layer that was suppressed in the growth plate has been recognized as an adverse effect of cisplatin in pediatric cancer survivors, the detailed pathological mechanism has not been elucidated. Sirtuin-1 (SIRT1) has been reported as an essential modulator of cartilage homeostasis, but its role in cisplatin-induced damage of chondrocytes remains unclear. In this study, we examined how cisplatin affected the expression of SIRT1 and cell viability. Next, we showed downregulation of SIRT1 after cisplatin treatment resulted in suppression of Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), leading to inhibition of Nrf2 nuclear translocation and subsequently decreased Heme oxygenase-1(HO-1) and NAD(P)H Quinone Dehydrogenase 1(NQO-1) expression. Blockage of the SIRT1/ PGC-1α axis not only increased oxidative stress with lower antioxidant SOD and GSH, but also contributed to mitochondrial dysfunction evidenced by the collapse of membrane potential and repression of mitochondrial DNA copy number and ATP. We also found that Cisplatin up-regulated the p38 phosphorylation, pro-inflammatory events and matrix metalloproteinases (MMPs) in chondrocytes through the SIRT1-modulated antioxidant manner. Collectively, our findings suggest that preservation of SIRT1 in chondrocytes may be a potential target to ameliorate growth plate dysfunction for cisplatin-receiving pediatric cancer survivors.

Original languageEnglish
Pages (from-to)2476-2486
Number of pages11
JournalEnvironmental Toxicology
Volume38
Issue number10
DOIs
Publication statusPublished - 2023 Oct

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Management, Monitoring, Policy and Law
  • Health, Toxicology and Mutagenesis

Fingerprint

Dive into the research topics of 'Cisplatin triggers oxidative stress, apoptosis and pro-inflammatory responses by inhibiting the SIRT1-mediated Nrf2 pathway in chondrocytes'. Together they form a unique fingerprint.

Cite this