Kashkar Hamid, Haefs Christiane, Shin Hwain, Hamilton-Dutoit Stephen J, Salvesen Guy S, Kronke Martin, Jurgensmeier Juliane M
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany.
J Exp Med. 2003 Jul 21;198(2):341-7. doi: 10.1084/jem.20021279.
The malignant Hodgkin and Reed-Sternberg cells of Hodgkin's lymphoma (HL) and HL-derived B cell lines were previously shown to be resistant to different apoptotic stimuli. We show here that cytochrome c fails to stimulate caspases-9 and -3 activation in cytosolic extracts of HL-derived B cells, which is due to high level expression of X-linked inhibitor of apoptosis (XIAP). Coimmunoprecipitation studies revealed that XIAP, apoptosis protease-activating factor-1, and caspase-3 are complexed in HL-derived B cell lysates. Even after stimulation with exogenous cytochrome c and dATP, XIAP impairs the proteolytic processing and activation of caspase-3. In cytosolic extracts, inhibition of XIAP by the second mitochondria-derived activator of caspases (Smac)/DIABLO, or immunodepletion of XIAP restores cytochrome c-triggered processing and activation of caspase-3. Smac or a Smac-derived agonistic peptide also sensitized intact HL-derived B cells for the apoptotic action of staurosporine. Finally, Hodgkin and Reed-Sternberg cells of primary tumor HL tissues also constitutively and abundantly express XIAP. The results of this paper suggest that high level XIAP expression is a hallmark of HL, which may play a crucial role in resistance to apoptosis.
先前研究表明，霍奇金淋巴瘤（HL）的恶性霍奇金和里德-施特恩贝格细胞以及HL衍生的B细胞系对不同的凋亡刺激具有抗性。我们在此表明，细胞色素c无法刺激HL衍生B细胞的胞质提取物中的半胱天冬酶-9和-3激活，这是由于X连锁凋亡抑制蛋白（XIAP）的高水平表达所致。免疫共沉淀研究显示，XIAP、凋亡蛋白酶激活因子-1和半胱天冬酶-3在HL衍生B细胞裂解物中形成复合物。即使在用外源性细胞色素c和dATP刺激后，XIAP仍会损害半胱天冬酶-3的蛋白水解加工和激活。在胞质提取物中，通过第二种线粒体衍生的半胱天冬酶激活剂（Smac）/DIABLO抑制XIAP，或通过免疫去除XIAP，可恢复细胞色素c触发的半胱天冬酶-3的加工和激活。Smac或Smac衍生的激动肽也使完整的HL衍生B细胞对星形孢菌素的凋亡作用敏感。最后，原发性肿瘤HL组织中的霍奇金和里德-施特恩贝格细胞也组成性且大量表达XIAP。本文结果表明，XIAP的高水平表达是HL的一个标志，可能在抗凋亡中起关键作用。
