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  • Title: Mechanism of beta 2-microglobulin-induced apoptosis in the K562 leukemia cell line, defective in major histocompatibility class 1.
    Author: Wu CH, Gordon JD, Zhong X, Safa AR.
    Journal: Anticancer Res; 2002; 22(5):2613-21. PubMed ID: 12529972.
    Abstract:
    BACKGROUND: It has been shown that exogenous beta 2-microglobulin (beta 2m) triggers significant apoptosis in several cell lines, but the molecular mechanism of beta 2m-induced apoptosis remains to be found. MATERIALS AND METHODS: To understand the mechanism of beta 2m-induced apoptosis, we added purified human beta 2m to cultures of K562 human chronic myelocytic leukemia cells, detected apoptosis by DNA fragmentation and annexin V binding assays, measured mitochondrial membrane potential (delta psi m), and used Z-VAD-fmk, a general inhibitor of caspases, inhibitors of caspases-1 and-3, as well as Western blot analysis to detect activated caspases. RESULTS: beta 2m-induced apoptosis was associated with decreased delta psi m K562 cells. Treatment with the general caspase inhibitor Z-VAD-fmk, as well as the caspase-1 inhibitor YVAD-CHO, significantly blocked beta 2m-induced apoptosis. However, Western blot analysis revealed that caspase-1 was intrinsically activated in untreated as well as beta 2m-treated K562 cells. Furthermore, beta 2m-induced apoptosis was not associated with the cleavage of caspase-3 as revealed by Western blot analysis, but was inhibited by an inhibitor of caspase-3, Z-DEVD-CHO, suggesting that not caspase-3, but a caspase-3-like enzyme may be involved in beta 2m-induced apoptosis. Western blot analysis also revealed that caspases-4, -8 and -9 were not activated during beta 2m-induced apoptosis in these cells. CONCLUSION: These results reveal that beta 2m-induced apoptosis in K562 cells occurs by a mechanism dependent on decreased mitochondrial delta psi m. Moreover, while caspase-1 activity may be one of the factors involved in beta 2m-induced apoptosis, activation of this caspase alone does not cause apoptosis, and other proapoptotic factors including activation of a caspase-3-like enzyme, independently of caspases-4, -8 and -9 activity, may be required to trigger apoptosis.
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