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

Autor: Thomas Klonisch, Thatchawan Thanasupawat, Maxwell Burg, Sabine Hombach-Klonisch, Jerry Krcek, Jason Beiko, Aleksandra Glogowska, Marshall Pitz, Guo-Jun Zhang
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
DNA Repair
Apoptosis
temozolomide
DNA Glycosylases
Receptors
G-Protein-Coupled
DNA damage repair
DNA Breaks
Double-Stranded
Molecular Targeted Therapy
Research Articles
Caspase 7
RXFP1
Chemistry
Kinase
Brain Neoplasms
Caspase 3
General Medicine
Base excision repair
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Oncology
Proto-Oncogene Proteins c-bcl-2
alkylating drug
Molecular Medicine
Adiponectin
medicine.drug
Research Article
Signal Transduction
STAT3 Transcription Factor
Receptors
Peptide
DNA repair
CTRP8
bcl-X Protein
lcsh:RC254-282
base excision repair
03 medical and health sciences
Cell Line
Tumor
Genetics
medicine
Humans
AP site
Antineoplastic Agents
Alkylating
Temozolomide
030104 developmental biology
DNA glycosylase
Drug Resistance
Neoplasm
Cancer research
Glioblastoma
MPG
Zdroj: Molecular Oncology
Molecular Oncology, Vol 12, Iss 9, Pp 1464-1479 (2018)
ISSN: 1878-0261
1574-7891
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: