Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program.
Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program.
复制标题
T-ALL 中对 APO-1 (CD95) 诱导的细胞凋亡的抵抗力是由 BCL-2 独立的抗细胞凋亡程序确定的。
作者：
K. Debatin;P. Krammer
选择性地诱导程序性细胞死亡，即细胞凋亡，可能代表着一种治疗癌症的新方法。针对神经生长因子(NGF)受体/肿瘤坏死因子(TNF)受体超家族成员细胞表面受体APO-1的抗APO-1单抗可诱导细胞凋亡。我们检测了儿童急性淋巴细胞白血病T淋巴细胞前体表型(T-ALL)细胞APO-1的表达及其对抗APO-1介导的细胞凋亡的敏感性。在30个T-ALL细胞系中，21个T-ALL细胞系和所有研究的T-ALL细胞系都表达Apo-1。然而，大多数APO-1阳性的T-ALL对抗APO-1介导的凋亡具有抵抗力。对抗APO-1介导的细胞凋亡的敏感性与APO-1在细胞表面的表达密度无关，也与Bcl2的含量无关。在大多数T-ALL中，耐药的T-ALL与蛋白质合成抑制剂放线菌酮一起孵育，逆转了对抗APO-1介导的细胞凋亡的耐药性并诱导了敏感性。这些数据表明，T-ALL对抗APO-1介导的凋亡的抵抗是由活跃的细胞程序维持的。逆转肿瘤对诱导细胞凋亡的敏感性可能为成功的治疗干预提供新的基础。
Selective induction of programmed cell death, apoptosis, may represent a new approach to the treatment of cancer. Apoptosis can be induced by the monoclonal antibody anti-APO-1 directed against the cell surface receptor APO-1, a member of the nerve growth factor (NGF) receptor/tumor necrosis factor (TNF) receptor superfamily. We determined APO-1 expression and sensitivity to anti-APO-1 mediated apoptosis in childhood acute lymphoblastic leukemia cells of T lymphocyte precursor phenotype (T-ALL). APO-1 was constitutively expressed by 21 of 30 T-ALL and by all T-ALL cell lines investigated. However, most APO-1 positive T-ALL were resistant to anti-APO-1 mediated apoptosis. Sensitivity to anti-APO-1 mediated apoptosis was independent of the density of APO-1 expression on the cell surface and independent of the amount of Bcl-2. Incubation of resistant T-ALL with the protein synthesis inhibitor cycloheximide reversed resistance and induced sensitivity to anti-APO-1 mediated apoptosis in most T-ALL. These data suggest that resistance to anti-APO-1 mediated apoptosis in T-ALL is maintained by an active cellular program. Reversion of resistance to sensitivity towards induction of apoptosis in tumors may provide a new basis for successful therapeutic intervention.