Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Department of Surgery, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Mol Oncol. 2018 Sep;12(9):1464-1479. doi: 10.1002/1878-0261.12349. Epub 2018 Aug 2.
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.
C1q/TNF 相关肽 8（CTRP8）最近被确定为致命性脑肿瘤胶质母细胞瘤（GBM）中 G 蛋白偶联受体 RXFP1 的新型配体。我们之前证明，CTRP8-RXFP1 配体-受体系统通过特定的 PI3 激酶和蛋白激酶 C 的磷酸化促进患者 GBM 和 U87 MG 细胞的迁移和基质侵袭。在这里，我们证明了 CTRP8 在保护人类 GBM 细胞免受替莫唑胺（TMZ）的 DNA 烷化损伤方面具有新的作用，TMZ 是用于治疗 GBM 的标准化疗药物。这种 CTRP8 在 GBM 细胞中的 DNA 保护作用需要功能性的 RXFP1-STAT3 信号级联。我们鉴定了 N-甲基嘌呤 DNA 糖基化酶（MPG），它是一种单功能糖苷酶，通过生成无嘌呤/无嘧啶（AP）位点来启动碱基切除修复途径，作为 GBM 中 CTRP8-RXFP1-STAT3 的新靶标。在 TMZ 暴露后，CTRP8 的处理减少了 GBM 细胞中 AP 位点和双链 DNA 断裂的形成。这种 CTRP8 效应独立于细胞 MGMT 水平，与 caspase 3/7 活性降低和人 GBM 的存活率增加有关。CTRP8 诱导的 RXFP1 激活导致人 GBM 中抗凋亡 Bcl 成员和 STAT3 靶标 Bcl-2 和 Bcl-XL 的细胞蛋白水平增加。总之，我们的结果表明，CTRP8-RXFP1 配体-受体系统通过一种新的多方面且具有临床相关性的机制在 GBM 中发挥 DNA 保护功能，以抵抗 TMZ 化疗应激。CTRP8-RXFP1-STAT3 轴是 TMZ 反应性/耐药性的一个新决定因素，也是提高人 GBM 治疗效果的新兴新药物靶点。
