C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma
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 cel...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-09-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12349 |
| _version_ | 1818412823333568512 |
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| author | Thatchawan Thanasupawat Aleksandra Glogowska Maxwell Burg Jerry Krcek Jason Beiko Marshall Pitz Guo‐Jun Zhang Sabine Hombach‐Klonisch Thomas Klonisch |
| author_facet | Thatchawan Thanasupawat Aleksandra Glogowska Maxwell Burg Jerry Krcek Jason Beiko Marshall Pitz Guo‐Jun Zhang Sabine Hombach‐Klonisch Thomas Klonisch |
| author_sort | Thatchawan Thanasupawat |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T10:53:26Z |
| format | Article |
| id | doaj.art-7a29a0b669f74ce7882b02597f2aa12d |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-14T10:53:26Z |
| publishDate | 2018-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-7a29a0b669f74ce7882b02597f2aa12d2022-12-21T23:05:05ZengWileyMolecular Oncology1574-78911878-02612018-09-011291464147910.1002/1878-0261.12349C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastomaThatchawan Thanasupawat0Aleksandra Glogowska1Maxwell Burg2Jerry Krcek3Jason Beiko4Marshall Pitz5Guo‐Jun Zhang6Sabine Hombach‐Klonisch7Thomas Klonisch8Department of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Surgery Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaChangJiang Scholar's Laboratory Shantou University Medical College ChinaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaDepartment of Human Anatomy and Cell Science Faculty of Medicine University of Manitoba Winnipeg CanadaThe 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.https://doi.org/10.1002/1878-0261.12349alkylating drugbase excision repairCTRP8DNA damage repairMPGRXFP1 |
| spellingShingle | Thatchawan Thanasupawat Aleksandra Glogowska Maxwell Burg Jerry Krcek Jason Beiko Marshall Pitz Guo‐Jun Zhang Sabine Hombach‐Klonisch Thomas Klonisch C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma Molecular Oncology alkylating drug base excision repair CTRP8 DNA damage repair MPG RXFP1 |
| title | C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma |
| title_full | C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma |
| title_fullStr | C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma |
| title_full_unstemmed | C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma |
| title_short | C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma |
| title_sort | c1q tnf related peptide 8 ctrp8 promotes temozolomide resistance in human glioblastoma |
| topic | alkylating drug base excision repair CTRP8 DNA damage repair MPG RXFP1 |
| url | https://doi.org/10.1002/1878-0261.12349 |
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