Dürkop Horst, Hirsch Burkhard, Hahn Corinna, Stein Harald
Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
J Mol Med (Berl). 2006 Feb;84(2):132-41. doi: 10.1007/s00109-005-0003-7. Epub 2005 Nov 25.
In this study, the expression of activated caspase-3 by the tumor cells of classical Hodgkin lymphoma (cHL), the Hodgkin-Reed-Sternberg (HRS) cells, is confirmed. This raises the question why caspase-3 does not kill HRS cells. There are only a few molecules, which are able to directly inhibit caspase-3. One of them is cIAP2. We show that cIAP2 is expressed in the HRS cells in 20 of 23 cHL cases by in situ hybridization. Suppression experiments with cIAP2 antisense RNA show that down-regulation of cIAP2 significantly reduces apoptosis resistance in cHL cell lines. cIAP2 overexpression appears to be unique for HRS cells since the tumor cells of non-Hodgkin lymphomas are nearly cIAP2-negative. We demonstrate that cIAP2 is inducible by CD30 stimulation in cHL cell lines of T-cell origin and anaplastic large cell lymphoma cell lines, whereas cHL cell lines of B-cell origin constitutively express cIAP2. Inhibition of cIAP2 expression by cIAP2 antisense RNA decreases resistance to apoptosis. The results indicate that cIAP2 contributes to the apoptosis resistance of HRS cells, mainly by inhibiting effector caspases. According to these findings, a therapeutical application of inhibitors of apoptosis proteins antagonists in cHL appears promising.
在本研究中，经典型霍奇金淋巴瘤（cHL）的肿瘤细胞，即霍奇金-里德-斯腾伯格（HRS）细胞中活化的半胱天冬酶-3的表达得到了证实。这就提出了一个问题，即为什么半胱天冬酶-3不能杀死HRS细胞。能够直接抑制半胱天冬酶-3的分子只有少数几种。其中之一是细胞凋亡抑制蛋白2（cIAP2）。我们通过原位杂交显示，在23例cHL病例中的20例中，HRS细胞中表达了cIAP2。用cIAP2反义RNA进行的抑制实验表明，cIAP2的下调显著降低了cHL细胞系中的凋亡抗性。cIAP2的过表达似乎是HRS细胞所特有的，因为非霍奇金淋巴瘤的肿瘤细胞几乎是cIAP2阴性的。我们证明，在T细胞起源的cHL细胞系和间变性大细胞淋巴瘤细胞系中，cIAP2可被CD30刺激诱导，而B细胞起源的cHL细胞系则组成性表达cIAP2。用cIAP2反义RNA抑制cIAP2的表达可降低对凋亡的抗性。结果表明，cIAP2主要通过抑制效应半胱天冬酶来促进HRS细胞的凋亡抗性。根据这些发现，凋亡蛋白拮抗剂抑制剂在cHL中的治疗应用似乎很有前景。
