Geserick P, Wang J, Feoktistova M, Leverkus M
Section of Molecular Dermatology, Department of Dermatology, Venerology, and Allergology, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
Cell Death Dis. 2014 Sep 11;5(9):e1412. doi: 10.1038/cddis.2014.379.
Tumour progression and therapy resistance in squamous cell carcinoma of the skin (SCC) is strongly associated with resistance to intrinsic mitochondrial apoptosis. We thus investigated the role of various anti-apoptotic Bcl-2 proteins for apoptosis protection in SCC using the BH3 agonist ABT737 that can overcome multidomain Bcl-2 protein protection. Sensitive SCC cells underwent rapid loss of mitochondrial membrane potential (MMP), subsequent apoptosis concomitant with caspase-3 activation and an early release of mitochondria-derived cytochrome c and smac/DIABLO. In contrast, ABT737 resistance in subsets of SCC cells was not explained by XIAP, important for protection from DR-induced apoptosis in SCC. Of note, ABT737 did not prime SCC cells to DR-induced apoptosis. Interestingly, the ratio of Mcl-1 and Noxa determined sensitivity to ABT737: loss of Mcl-1 rendered resistant cells sensitive to ABT737, whereas loss of Noxa promoted resistance in sensitive cells. In line, suppression of Mcl-1 by the pan-Bcl-2 inhibitor Obatoclax or overexpression of Noxa rendered resistant SCC cells sensitive to BH3 mimetics. Our data indicate that targeting of the Mcl-1/Noxa axis is important to overcome resistance to mitochondrial apoptosis in SCC. Therefore, combination treatment of ABT737 or derivatives with Mcl-1 inhibitors, or inducers of Noxa, may represent a novel option of targeted therapy in metastatic SCC of the skin.
皮肤鳞状细胞癌（SCC）中的肿瘤进展和治疗耐药性与对内在线粒体凋亡的抗性密切相关。因此，我们使用能够克服多结构域Bcl-2蛋白保护作用的BH3激动剂ABT737，研究了各种抗凋亡Bcl-2蛋白在SCC细胞凋亡保护中的作用。敏感的SCC细胞线粒体膜电位（MMP）迅速丧失，随后发生凋亡，伴随半胱天冬酶-3激活以及线粒体来源的细胞色素c和smac/DIABLO的早期释放。相比之下，SCC细胞亚群中对ABT737的耐药性不能用XIAP来解释，XIAP对保护SCC细胞免受死亡受体（DR）诱导的凋亡很重要。值得注意的是，ABT737不能使SCC细胞对DR诱导的凋亡产生致敏作用。有趣的是，Mcl-1与Noxa的比例决定了对ABT737的敏感性：Mcl-1缺失使耐药细胞对ABT737敏感，而Noxa缺失则使敏感细胞产生耐药性。同样，泛Bcl-2抑制剂Obatoclax对Mcl-1的抑制或Noxa的过表达使耐药的SCC细胞对BH3模拟物敏感。我们的数据表明，靶向Mcl-1/Noxa轴对于克服SCC中线粒体凋亡的抗性很重要。因此，将ABT737或其衍生物与Mcl-1抑制剂或Noxa诱导剂联合治疗，可能代表了皮肤转移性SCC靶向治疗的一种新选择。
