4-Acetyl-Antroquinonol B Improves the Sensitization of Cetuximab on Both Kras Mutant and Wild Type Colorectal Cancer by Modulating the Expression of Ras/Raf/miR-193a-3p Signaling Axis
| Autor: | Chun Chih Huang, Li Deng, Yi Cheng Chu, Ming Yao Chen, Tung Yao Tsai, Yew Min Tzeng, Chi Tai Yeh, Vijesh Kumar Yadav |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Ubiquinone Colorectal cancer Mutant Apoptosis medicine.disease_cause Mice Antineoplastic Agents Immunological 0302 clinical medicine cetuximab Tumor Cells Cultured 4-AAQB Epidermal growth factor receptor Biology (General) Spectroscopy Mice Inbred BALB C Cetuximab biology Drug Synergism General Medicine Prognosis Computer Science Applications Gene Expression Regulation Neoplastic Chemistry 030220 oncology & carcinogenesis Drug Therapy Combination Female raf Kinases KRAS Colorectal Neoplasms medicine.drug QH301-705.5 Mice Nude colorectal cancer Article Catalysis Proto-Oncogene Proteins p21(ras) Inorganic Chemistry resistance 03 medical and health sciences Gentamicin protection assay Biomarkers Tumor medicine Animals Humans Physical and Theoretical Chemistry Molecular Biology neoplasms QD1-999 Cell Proliferation Organic Chemistry Wild type KRAS mutation medicine.disease Xenograft Model Antitumor Assays digestive system diseases MicroRNAs 030104 developmental biology Cell culture Mutation ras Proteins Cancer research biology.protein |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 7508, p 7508 (2021) International Journal of Molecular Sciences Volume 22 Issue 14 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | The KRAS mutation is one of the leading driver mutations in colorectal cancer (CRC), and it is usually associated with poor prognosis and drug resistance. Therapies targeting the epidermal growth factor receptor (EFGR) are widely used for end-stage CRC. However, patients with KRAS mutant genes cannot benefit from this therapy because of Ras signaling activation by KRAS mutant genes. Our previous study revealed the anti-proliferative effect of 4-acetyl-antroquinonol B (4-AAQB) on CRC cells, but whether the drug is effective in KRAS-mutant CRC remains unknown. We screened CRC cell lines harboring the KRAS mutation, namely G12A, G12C, G12V and G13D, with one wild type cell line as the control SW1463 and Caco-2 cell lines were used for further experiments. Sulforhodamine B assays, together with the clonogenicity and invasion assay, revealed that KRAS-mutant SW1463 cells were resistant to cetuximab however, 4-AAQB treatment effectively resensitized CRC cells to cetuximab through the reduction of colony formation, invasion, and tumorsphere generation and of oncogenic KRAS signaling cascade of CRC cells. Thus, inducing cells with 4-AAQB before cetuximab therapy could resensitize KRAS-mutant, but not wild-type, cells to cetuximab. Therefore, we hypothesized that 4-AAQB can inhibit KRAS. In silico analysis of the publicly available GEO (GSE66548) dataset of KRAS-mutated versus KRAS wild-type CRC patients confirmed that miR-193a-3p was significantly downregulated in the former compared with the latter patient population. Overexpression of miR-193a-3p considerably reduced the oncogenicity of both CRC cells. Furthermore, KRAS is a key target of miR-193a-3p. In vivo treatment with the combination of 4-AAQB and cetuximab significantly reduced the tumor burden of a xenograft mice model through the reduction of the expression of oncogenic markers (EGFR) and p-MEK, p-ERK, and c-RAF/p-c-RAF signaling, with the simultaneous induction of miR-193a-3p expression in the plasma. In summary, our findings provide strong evidence regarding the therapeutic effect of 4-AAQB on KRAS-mutant CRC cells. Furthermore, 4-AAQB effectively inhibits Ras singling in CRC cells, through which KRAS-mutant CRC can be resensitized to cetuximab. |
| Databáze: | OpenAIRE |
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