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http://ir.nhri.org.tw/handle/3990099045/14501
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| Title: | CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer |
| Authors: | Hsieh, CC;Hsu, SH;Lin, CY;Liaw, HJ;Li, TW;Jiang, KY;Chiang, NJ;Chen, SH;Lin, BW;Chen, PC;Chan, RH;Lin, PC;Yeh, YM;Shen, CH |
| Contributors: | National Institute of Cancer Research |
| Abstract: | BACKGROUND: Colorectal cancer (CRC), the most common cancer type, causes high morbidity and mortality. Patients who develop drug resistance to oxaliplatin-based regimens have short overall survival. Thus, identifying molecules involved in the development of oxaliplatin resistance is critical for designing therapeutic strategies. METHODS: A proteomic screen was performed to reveal altered protein kinase phosphorylation in oxaliplatin-resistant (OR) CRC tumour spheroids. The function of CHK2 was characterised using several biochemical techniques and evident using in vitro cell and in vivo tumour models. RESULTS: We revealed that the level of phospho-CHK2(Thr68) was elevated in OR CRC cells and in ~30% of tumour samples from patients with OR CRC. We demonstrated that oxaliplatin activated several phosphatidylinositol 3-kinase-related kinases (PIKKs) and CHK2 downstream effectors and enhanced CHK2/PARP1 interaction to facilitate DNA repair. A phosphorylation mimicking CHK2 mutant, CHK2T68D, but not a kinase-dead CHK2 mutant, CHK2D347A, promoted DNA repair, the CHK2/PARP1 interaction, and cell growth in the presence of oxaliplatin. Finally, we showed that a CHK2 inhibitor, BML-277, reduced protein poly(ADP-ribosyl)ation (PARylation), FANCD2 monoubiquitination, homologous recombination and OR CRC cell growth in vitro and in vivo. CONCLUSION: Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC. |
| Date: | 2022-11 |
| Relation: | British Journal of Cancer. 2022 Nov;127(9):1615-1628. |
| Link to: | http://dx.doi.org/10.1038/s41416-022-01946-9 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0007-0920&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000843444900008 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85136807648 |
| Appears in Collections: | [沈哲宏] 期刊論文
[陳尚鴻] 期刊論文
[姜乃榕] 期刊論文
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| PUB35999268.pdf | | 7736Kb | Adobe PDF | 172 | View/Open |
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