1. Academic Validation
  2. BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes

BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes

  • Biochem Biophys Res Commun. 2022 Jun 18;609:93-99. doi: 10.1016/j.bbrc.2022.03.155.
Guihao Wu 1 Cifeng Zhang 1 Lingjun Xu 1 Hongce Chen 2 Xuhong Fan 1 Beini Sun 2 Qiling Tang 2 Yongtong Zhan 1 Tongsheng Chen 2 Xiaoping Wang 3
Affiliations

Affiliations

  • 1 Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
  • 2 MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 3 Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. Electronic address: txp2938@jnu.edu.cn.
Abstract

Osteoarthritis occurs when the number of senescent chondrocytes in the joints reaches an intolerable level. The purpose of our study was to explore the therapeutic effect and mechanism of action of A-1331852 in osteoarthritis. Doxorubicin and etoposide were used to induce cell senescence as determined by the cessation of cell proliferation, augmented senescence-associated beta-galactosidase (SA-β-Gal) staining, and increased p53 expression levels. The CCK-8 cytotoxicity assay and SA-β-Gal staining demonstrated that Bcl-xL inhibitors could selectively remove senescent chondrocytes without damaging healthy chondrocytes. A-1331852 induced caspase-dependent death of senescent chondrocytes with decreased mitochondrial membrane potential, nuclear concentration, plasma membrane rupture, and PARP cleavage. Most importantly, A-1331852 upregulated Bak expression levels, indicating that Bak plays a key role in the A-1331852-induced Apoptosis of senescent chondrocytes. Live-cell fluorescence resonance energy transfer showed that A-1331852 detached the binding of Bcl-xL to Bak and promoted the oligomerization of Bak on the mitochondrial membrane. In conclusion, this study provides the first evidence that A-1331852 selectively promotes Apoptosis in senescent chondrocytes by interfering with the interaction between Bcl-xL and Bak.

Keywords

A-1331852; Apoptosis; BAK; Bcl-xL; Osteoarthritis; Senescence.

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