Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, Canada.
Department of Surgery, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, Canada.
Mol Oncol. 2022 Jan;16(2):368-387. doi: 10.1002/1878-0261.12981. Epub 2021 Jun 18.
C1q tumor necrosis factor-related peptide 8 (CTRP8) is the least studied member of the C1Q-TNF-related peptide family. We identified CTRP8 as a ligand of the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8-RXFP1 ligand-receptor system protects human GBM cells against the DNA-alkylating damage-inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1-STAT3 signaling cascade and targeted the monofunctional glycosylase N-methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ-induced DNA-damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti-apoptotic BCl-2 and BCL-XL. Here, we have identified Janus-activated kinase 3 (JAK3) as a novel member of a novel CTRP8-RXFP1-JAK3-STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F-actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N-Wiskott-Aldrich syndrome protein/Arp3/4 and actin elongation factor profilin-1. The activation of the RXFP1-JAK3-STAT3-Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin-2, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F-actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F-actin remodeling and pro-migratory activities promoted by the novel RXFP1-JAK3-STAT3-Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM.
C1q 肿瘤坏死因子相关肽 8（CTRP8）是 C1Q-肿瘤坏死因子相关肽家族中研究最少的成员。我们在多形性胶质母细胞瘤（GBM）中发现 CTRP8 是 G 蛋白偶联受体松弛素家族肽受体 1（RXFP1）的配体。CTRP8-RXFP1 配体-受体系统可保护人 GBM 细胞免受 DNA-烷化损伤诱导的替莫唑胺（TMZ）的影响，TMZ 是治疗 GBM 患者的首选药物。CTRP8 的 DNA 保护作用依赖于功能性 RXFP1-STAT3 信号级联，并且针对单功能糖苷酶 N-甲基嘌呤 DNA 糖基化酶（MPG），以更有效地修复 TMZ 诱导的 DNA 损伤部位的碱基切除修复。CTRP8 通过上调抗凋亡 BCl-2 和 BCL-XL 也改善了 GBM 细胞的存活率。在这里，我们鉴定出 Janus 激活激酶 3（JAK3）是新型 CTRP8-RXFP1-JAK3-STAT3 信号级联的新成员，该级联导致细胞蛋白含量增加和小 Rho GTPase Cdc42 的活性增加。这与 F-肌动蛋白的显著重塑和 GBM 运动性增加有关。Cdc42 对于肌动蛋白成核复合物 N-Wiskott-Aldrich 综合征蛋白/Arp3/4 和肌动蛋白伸长因子 Profilin-1 的上调至关重要。两种 RXFP1 激动剂 CTRP8 和松弛素-2 通过激活 RXFP1-JAK3-STAT3-Cdc42 轴引起广泛的丝状伪足形成。这与 ezrin 的活性增强相吻合，ezrin 是将 F-肌动蛋白固定到质膜上的关键因素，并且抑制了束丝切割肌动蛋白的肌动蛋白丝切割活性。新型 RXFP1-JAK3-STAT3-Cdc42 轴促进的 F-肌动蛋白重塑和促迁移活性被 JAK3 抑制剂托法替尼和 STAT3 抑制剂 STAT3 抑制剂 VI 阻断。这为设计具有更好脑渗透性的 JAK3 和 STAT3 抑制剂提供了新的依据，用于临床治疗 GBM 的普遍脑侵袭性。
