C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

Abstract

The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

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

“…S1A,C) and RLN2 (Fig. S1H) [45,59]. Next, we investigated the Janusactivated kinase (JAK) signaling factors, which are known to facilitate signal transduction events by several cytokine receptors and G protein-coupled receptors upstream of their phosphorylation target STAT3 [60,61].…”

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres

“…Several genes included in these regions could hide an important role in the progression of glioma, as reported by the literature. For example, the expression level of the EXT2 gene is increased in glioblastoma [ 60 ]; C1QTNF8 promotes temozolomide resistance [ 61 ]; CACNA1H promotes GBM cell proliferation and migration [ 62 ]. Finally, we noticed that the CNAs in gains are more represented in PBZ samples, compared to the losses.…”

Overexpression of C1QTNF6 Predicts a Poor Prognosis in Bladder Cancer

“…The C1QTNF family has a highly conserved c-terminal complementary C1q domain consisting of 16 CTRP members, including C1QTNF 1-9,9b, 10-15 [13]. All C1QTNF members are secreted proteins that are widely expressed in a variety of tissues and cell types and are involved in a variety of biological processes, including host defense, in ammation, apoptosis, autoimmunity, cell differentiation, organogenesis, hibernation, and insulin-resistant obesity [14][15][16][17][18][19]. C1QTNF6, as a member of C1QTNF family, was demonstrated to be associated with carcinogenesis in digestive cancers, however, the biological functions in bladder cancer still required investigating.…”