Cetraro Pierina, Plaza-Diaz Julio, MacKenzie Alex, Abadía-Molina Francisco
Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Armilla, 18016 Granada, Spain.
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Cancers (Basel). 2022 Mar 25;14(7):1671. doi: 10.3390/cancers14071671.
The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer.
凋亡抑制蛋白（IAP）家族具有通过不同机制抑制程序性细胞死亡的能力；此外，其一些成员已成为免疫反应的重要调节因子。对半胱天冬酶的直接和间接作用或对生存途径的调节，如活化B细胞核因子κB（NF-κB），都与其作用的介导有关。因此，凋亡抑制蛋白（IAPs）的异常表达可导致凋亡失调，促进不同病理状况的发展。在几种癌症类型中，IAPs过表达，而其天然拮抗剂——第二线粒体衍生的半胱天冬酶激活剂（Smac）似乎下调，这可能导致对传统疗法产生耐药性。最近开发的Smac模拟物可对抗IAP活性，并在使癌细胞重新对凋亡敏感方面显示出前景。鉴于Smac模拟物作为单一疗法的效果有限，越来越多地探索将这些化合物与其他治疗方式联合使用。肿瘤微环境中存在的分子如肿瘤坏死因子-α（TNF-α）的调节被认为有助于IAP抑制的假定治疗效果，尽管已发表的结果并未始终显示这一点，这突出了IAPs与癌症之间复杂的相互作用。
