癌症中细胞骨架细丝蛋白 A C 末端片段的靶向裂解。
Targeting Cleavage of C-Terminal Fragment of Cytoskeletal Filamin A in Cancers.
发表日期：2024 Aug 21
作者：
Ozgur Cakici, Sashidar Bandaru, Grace Yankun Lee, Dyar Mustafa, Levent M Akyürek
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
人类癌症表达肌动蛋白结合细胞骨架细丝蛋白 A (FLNA) 蛋白的水平发生改变。哺乳动物中的 FLNA 在其 N 末端包含一个肌动蛋白结合结构域，其后是 24 个免疫球蛋白样重复模块，在重复 15-16 和 23-24 之间被两个铰链区中断。这些铰链区的裂解产生天然存在的 FLNA C 端 90 kDa 片段 (FLNACT)，该片段与具有不同功能的多种蛋白质发生物理相互作用。这种切割导致肌动蛋白细胞骨架重塑，进而有助于细胞信号传导、转录因子和核受体的核质穿梭，以及它们转录活性的调节，这对癌症的发生和进展很重要。因此，最近的研究提出阻断 FLNA 裂解作为癌症治疗的一种手段。在这里，我们更新了不同方法如何靶向 FLNA 裂解及其对未来人类癌症治疗的潜在影响。
Human cancers express altered levels of actin-binding cytoskeletal filamin A (FLNA) protein. FLNA in mammals consists of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules interrupted by two hinge regions between repeats 15-16 and 23-24. Cleavage of these hinge regions produces a naturally occurring C-terminal 90 kDa fragment of FLNA (FLNACT) that physically interacts with multiple proteins with diverse functions. This cleavage leads to actin cytoskeleton remodeling, which in turn contributes to cellular signaling, nucleocytoplasmic shuttling of transcriptional factors and nuclear receptors, and regulation of their transcriptional activities that are important for initiation and progression of cancers. Therefore, recent studies have proposed blocking FLNA cleavage as a means of cancer therapy. Here, we update how FLNA cleavage has been targeted by different approaches and their potential implications for future treatment of human cancers.