Dataset Information

CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.

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.

SUBMITTER: Hsieh CC

PROVIDER: S-EPMC9596403 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.

Hsieh Chi-Che CC Hsu Sen-Huei SH Lin Chih-Yu CY Liaw Hung-Jiun HJ Li Ting-Wei TW Jiang Kuan-Ying KY Chiang Nai-Jung NJ Chen Shang-Hung SH Lin Bo-Wen BW Chen Po-Chuan PC Chan Ren-Hao RH Lin Peng-Chan PC Yeh Yu-Min YM Shen Che-Hung CH

British journal of cancer 20220823 9

<h4>Background</h4>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.<h4>Methods</h4>A proteomic screen was performed to reveal altered protein kinase phosphorylation in oxaliplatin-resistant (OR) CRC tumour spheroids. The function ...[more]

PMID: 35999268

Similar Datasets

Project description:BackgroundDoctors have always been overwhelmed by tumor drug resistance because it is a major challenge in the clinical treatment of tumors. Cellular senescence has a strong relationship with the development of tumor drug resistance. Herein, we aimed to explore new regulatory factors involved in the aging process of colorectal cancer (CRC) cells and assess the effect of cellular senescence on CRC drug resistance.MethodsGenes associated with cellular senescence for anticipating regulatory factors were first used, and the regulatory molecules of survival significance were then identified based on the results of public database analysis. The effects of E2F translation factor 1 (E2F1) on CRC cell viability, invasion, migration, and cellular senescence processes were assessed through 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-Ethynyl-2'-deoxyuridine (EdU), Transwell, scar repairining, β-galactosidase staining, and cell immunofluorescence assays, respectively. Overexpression or silencing plasmids were used for transfecting HCT116 or OXA-HCT116 to assess the effect of E2F1 on the senescence process and drug resistance in CRC cells.ResultsOn combining the database analysis results with those of our studies, we found that E2F1 was a critical regulator of cellular senescence in CRC. In the in vitro experiments, the E2F1 overexpression significantly stimulated the proliferation, invasion, and migration of CRC cells and even reduced oxaliplatin-induced senescence, further enhancing their resistance to oxaliplatin. Conversely, the tumorigenesis of colorectal cancer was repressed after the suppression of E2F1. Furthermore, CRC cells, which were otherwise resistant to oxaliplatin, also showed senescent phenotypes.ConclusionsOur results suggest that E2F1 suppresses the aging of CRC cells and tumor cells develop resistance to oxaliplatin through high E2F1 expression. Moreover, E2F1 may act as a possible target for oxaliplatin resistance studies.

Dataset Information

CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.

Background

Methods

Results

Conclusion

Publications

CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets