Frazzi Raffaele
Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Viale Risorgimento 80, Reggio Emilia, Italy.
Cell Biosci. 2021 Jan 7;11(1):8. doi: 10.1186/s13578-020-00521-0.
The evasion from apoptosis is a common strategy adopted by most tumors, and inhibitors of apoptosis proteins (IAPs) are among the most studied molecular and therapeutic targets. BIRC3 (cellular IAP2) and BIRC5 (survivin) are two of the eight members of the human IAPs family. This family is characterized by the presence of the baculoviral IAP repeat (BIR) domains, involved in protein-protein interactions. In addition to the BIR domains, IAPs also contain other important domains like the C-terminal ubiquitin-conjugating (UBC) domain, the caspase recruitment (CARD) domain and the C-terminal Ring zinc-finger (RING) domain.
BIRC3 and BIRC5 have been characterized in some solid and hematological tumors and are therapeutic targets for the family of drugs called "Smac mimetics". Many evidences point to the pro-survival and antiapoptotic role of BIRC3 in cancer cells, however, not all the data are consistent and the resulting picture is heterogeneous. For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients. BIRC3 inactivation has also been associated to chemoimmunotherapy resistance. On the contrary, the progression from low grade gliomas to high grade gliomas is accompanied by BIRC3 expression increase, which bears relevant prognostic consequences. Due to the relationship between BIRC3, MAP3K14 and the non-canonical NF-kB pathway, BIRC3 inactivation bears consequences also on the tumor cells relying on NF-kB pathway to survive. BIRC5, on the contrary, is commonly considered an anti-apoptotic molecule, promoting cell division and tumor progression and it is widely regarded as potential therapeutic target.
The present manuscript collects and reviews the most recent literature concerning the role played by BIRC3 and BIRC5 in cancer cells, providing useful information for the choice of the best therapeutic targets.
逃避细胞凋亡是大多数肿瘤采用的常见策略，凋亡抑制蛋白（IAPs）是研究最多的分子和治疗靶点之一。BIRC3（细胞IAP2）和BIRC5（生存素）是人类IAPs家族八个成员中的两个。该家族的特征是存在杆状病毒IAP重复（BIR）结构域，参与蛋白质-蛋白质相互作用。除了BIR结构域，IAPs还包含其他重要结构域，如C末端泛素结合（UBC）结构域、半胱天冬酶募集（CARD）结构域和C末端环状锌指（RING）结构域。
BIRC3和BIRC5已在一些实体瘤和血液肿瘤中得到表征，是一类名为“Smac模拟物”的药物家族的治疗靶点。许多证据表明BIRC3在癌细胞中具有促生存和抗凋亡作用，然而，并非所有数据都是一致的，结果情况各异。例如，慢性淋巴细胞白血病患者中因缺失或点突变导致的BIRC3基因失活与无进展生存期缩短和预后不良始终相关。BIRC3失活也与化疗免疫治疗耐药有关。相反，低级胶质瘤向高级胶质瘤的进展伴随着BIRC3表达增加，这具有相关的预后后果。由于BIRC3、MAP3K14与非经典NF-κB途径之间的关系，BIRC3失活也会对依赖NF-κB途径存活的肿瘤细胞产生影响。相反，BIRC5通常被认为是一种抗凋亡分子，促进细胞分裂和肿瘤进展，并且被广泛视为潜在的治疗靶点。
本手稿收集并综述了关于BIRC3和BIRC5在癌细胞中作用的最新文献，为选择最佳治疗靶点提供了有用信息。
