Novel CTRP8‐RXFP1‐JAK3‐STAT3 axis promotes Cdc42‐dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells

Abstract

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.

PLEK2 mediates metastasis and invasion via α5‐nAChR activation in nicotine‐induced lung adenocarcinoma

“…52 Several studies showed that the effect of CFL1 on the cellular activity is mediated by STAT3. 53,54 We confirmed that CFL1 expression was mediated by STAT3 (Supp.…”

Cofilin Acts as a Booster for Progression of Malignant Tumors Represented by Glioma

“…Using specific Rho kinase inhibitors targeting this pathway reduces the level of phosphorylated myosin II and cofilin, subsequently prevents tumor cell migration by inhibiting the dynamic assembly of f-actin structures. 101 P2Y2 nucleotide receptor (P2Y2R), 129 reticulon-4 isoform A (Nogo-A), 130 electroneutral Na + -K + -2Cl − -co-transporter1 (NKCC1), 131 miR-451, 132 C1q tumor necrosis factor-related peptide8 (CTRP8), 133 miR-29a/b/c 134 etc. are considered regulating phosphorylated LIMK1/2 and cofilin through targeting different members of Rho family of GTPases, including Rac1, the member A of Rho (RhoA) and CDC42, subsequently regulating glioma cell migration and invasion.…”

C1q and central nervous system disorders

“…Binding of the leucine-rich G protein-coupled relaxin receptor RXFP1 to C1q-tumor necrosis factor-related protein 8 (CTRP8) ligand mediates increased GBM cell migration, protein kinase C pathway activation, and lysosomal protease cathepsin B production in glioblastoma progenitor cells ( 158 – 160 ). Additionally, RXFP1-CTRP8 promotes actin cytoskeletal remodeling and filopodia formation through STAT3 signaling, further enhancing glioblastoma migration ( 89 ). C1q/TNF-related protein 1 (CTRP1), a member of the CTRP family, is strongly correlated with glioblastoma multiforme (GBM) and can regulate CCL2 expression, promoting tumor progression ( 91 ).…”