Liu Yadong,Zhang Guiqi,Wu Jiani,Meng Yi,Hu Jianyu,Fu Hao,Yang Dongfang
Intervertebral disc degeneration (IDD) diseases are common and frequent diseases in orthopedics. The caspase recruitment domain (CARD) and membrane-associated guanylate kinase-like protein 3 (CARMA3) is crucial in the activation of the NF-κB pathway. However, the biological function of CARMA3 in IDD remains unknown. Here, CARMA3 expression was elevated in nucleus pulposus (NP) tissues of IDD rats and nutrient deprivation (ND)-induced NP cells. The main pathological manifestations observed in IDD rats were shrinkage of the NP, reduction of NP cells, fibrosis of NP tissues, and massive reduction of proteoglycans. These changes were accompanied by a decrease in the expression of collagen II and aggrecan, an increase in the expression of the extracellular matrix (ECM) catabolic proteases MMP-3, MMP-13, and metalloprotease with ADAMTS-5, and an increase in the activity of the pro-apoptotic protease caspase-3. The expression of p-IκBα Ser32/36 and p-p65 Ser536 was also upregulated. However, these effects were reversed with the knockdown of CARMA3. Mechanistically, CARMA3 bound to BCL10 and MALT1 to form a signalosome. Knockdown of CARMA3 reduced the CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation. CARMA3 activated the NF-κB signaling pathway in a manner that bound to BCL10 and MALT1 to form a signalosome, which affects NP cell damage and is involved in the development of IDD. This supports CARMA3-BCL10-MALT1-NF-κB as a promising targeting axis for the treatment of IDD.
Peng-Tuo Xiao,Chang-Feng Li,Yuan-Da Liu,Jing Zhong,Xi-Lun Cui,Chang Liu,Wei Yang
BACKGROUND Colorectal cancer (CRC) is a major global health burden. B cell CLL/lymphoma 10 (BCL10), a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase complexes, is upregulated in CRC and associated with poor patient prognosis, suggesting its potential role in CRC development and progression. Cuproptosis, a novel form of programmed cell death, has emerged as a promising therapeutic strategy for cancer. AIM To explore the role of BCL10 in regulating the sensitivity of CRC cells to cuproptosis. METHODS A series of in vitro and in vivo experiments were conducted using CRC cell lines and CRC mouse models to evaluate the effects of BCL10 on CRC cell proliferation, migration, invasion, and sensitivity to copper-induced cell death. Mechanistic studies were performed to elucidate the underlying molecular pathways. RESULTS BCL10 promoted CRC cell proliferation, migration, and invasion, while its knockdown had the opposite effects. BCL10 also influenced the sensitivity of CRC cells to cuproptosis, with BCL10 overexpression enhancing resistance and its knockdown increasing sensitivity. The mechanism involved BCL10 modulating the expression of DLAT, a key protein in the copper-induced cell death pathway, through activation of the nuclear factor kappa-B (NF-κB) signaling pathway. CONCLUSION BCL10 promotes CRC growth and regulates the sensitivity of CRC cells to cuproptosis by activating the NF-κB signaling pathway and modulating DLAT expression. These findings provide a molecular basis for developing BCL10-targeted therapies for CRC.
危险品化学品经营许可证（带存储）