Functional role of C1Q-TNF related peptide 8 (CTRP8)-binding RXFP1 in brain tumors

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2017-06, 2015-08, 2013-12
Thanasupawat, Thatchawan
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FEBS press
John Wiley & Sons
Glioblastoma (GB) is the most common and highly aggressive form of primary brain cancer. GB invasiveness and the development of treatment resistance are major clinical challenges. The underlying mechanisms remain poorly understood. We identified the presence of relaxin family peptide receptor1 (RXFP1) and discovered C1q-tumor necrosis factor-related peptide 8 (CTRP8) as a novel RXFP1 ligand in GB cells. I demonstrate a novel mechanistic link between the activated RXFP1 and DNA protection against alkylating drugs in human GB. Like relaxin (RLN2), CTRP8 was able to bind to and activate RXFP1 in GB cells. This resulted in STAT3 signaling and enhanced the protection of cells from temozolomide (TMZ)-induced DNA damage. TMZ chemoresistance is a common occurrence and a major cause for fatal outcome in GB. TMZ induced DNA damage is repaired by the base excision repair (BER) pathway. Impaired BER eventually leads to double strand DNA (dsDNA) breaks which are detected by phosphorylated γH2AX and comet assay. CTRP8-RXFP1 activation was able to protect cells from TMZ-induced DNA damage and enhanced GB survival. Activation of RXFP1 caused the STAT3-dependent up-regulation of the BER member N-methylpurine-DNA glycosylase (MPG) which has a key role in the first step of BER. RXFP1-STAT3 signaling increased both MPG protein content and activity. High Mobility Group AT-hook protein 2 (HMGA2) is a non-histone chromatin protein which is a BER member containing AP/dRP lyase activity. HMGA2 protein expression increases upon CTRP8/RLN2-RXFP1-STAT3 pathway activation. The presence of HMGA2 reduced TMZ-induced DNA damage as detected by γH2AX. The knockdown of HMGA2 sensitized GB cells to TMZ and increased apoptosis. Dovitinib, (DOV) is a FDA-approved agent. DOV enhanced TMZ sensitivity by downregulating key factors in BER and MGMT. DOV inhibited phospho-STAT3Tyr705-LIN28A which are upstream regulators of HMGA2. HMGA2 played an importance role to promote TMZ chemoresistance. The sequential treatment with DOV and TMZ decreased in cell viability in GB cells. Results indicate a novel role for the CTRP8-RXFP1 ligand-receptor system in STAT3-dependent TMZ chemoresistance, and survival. I applied DOV to sensitize GB cells to TMZ-induced DNA damage to provide a new and attractive therapeutic target to improve TMZ efficacy in GB patients.
Molecular biology of cancer, Chemoresistance, Glioblastoma
Thanasupawat, T., Natarajan, S., Rommel, A., Glogowska, A., Bergen, H., Krcek, J., . . . Hombach-Klonisch, S. (2017). Dovitinib enhances temozolomide efficacy in glioblastoma cells. Mol Oncol, 11(8), 1078-1098. doi: 10.1002/1878-0261.12076
Thanasupawat, T., Glogowska, A., Burg, M., Wong, G. W., Hoang-Vu, C., Hombach-Klonisch, S., & Klonisch, T. (2015). RXFP1 is Targeted by Complement C1q Tumor Necrosis Factor-Related Factor 8 in Brain Cancer. Front Endocrinol (Lausanne), 6, 127. doi: 10.3389/fendo.2015.00127
Glogowska, A., Kunanuvat, U., Stetefeld, J., Patel, T. R., Thanasupawat, T., Krcek, J., . . . Klonisch, T. (2013). C1q-tumour necrosis factor-related protein 8 (CTRP8) is a novel interaction partner of relaxin receptor RXFP1 in human brain cancer cells. J Pathol, 231(4), 466-479. doi: 10.1002/path.4257