Knockdown of ADAM17 inhibits cell proliferation and increases oxaliplatin sensitivity in HCT-8 colorectal cancer through EGFR-PI3K-AKT activation
| Autor: | Guanghua Yang, Xuechao Han, Qi Zhang, Zhipeng Ge, Guozhi Zhang, Changyou Wang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Biophysics Down-Regulation Antineoplastic Agents Apoptosis ADAM17 Protein Biochemistry Small hairpin RNA Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Gene knockdown Akt/PKB signaling pathway Cell growth Chemistry Cell Biology ErbB Receptors Oxaliplatin 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer research Colorectal Neoplasms Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Biochemical and Biophysical Research Communications. 503:2333-2339 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2018.06.158 |
| Popis: | We investigated the role of a disintegrin and metalloproteinase 17 (ADAM17) in chemo resistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of ADAM17. CRC tissues with corresponding adjacent normal tissues were collected. The mRNA and protein expression of ADAM17 in tissues were detected by RT-qPCR, immunohistochemistry and Western blot. The prognostic impact of ADAM17 expression were then validated in TCGA database to confirm the results. Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal cancer cell line by exposing cell to increasing concentrations of L-OHP. MTT were used to evaluate the resistance to L-OHP. Subsequently, Knockdown of ADAM17 in HCT-8 and HCT-8/L-OHP cells to explore the mechanism through which ADAM17 shRNA reverses L-OHP resistance. Our result showed that ADAM17 was higher expression in the cancerous tissue and related to the chemosensitivity. Moreover, ADAM17 shRNA, AG1478 and LY294002 could inhibit cell proliferation, induce apoptosis and increase oxaliplatin sensitivity in HCT-8/L-OHP and parental colorectal cancer cell line, but nonsense shRNA did not show this effect. Western blot analysis further confirmed that EGFR/PI3K/AKT signaling pathway is involved in ADAM17 shRNA inhibiting proliferation and chemosensitivity of HCT-8/L-OHP and HCT-8 cells. The present study provides the evidence that downregulation of ADAM17 could increase the sensitivity to chemotherapy, inhibit cell proliferation, induce apoptosis, and reverse oxaliplatin resistance via suppression of the EGFR/PI3K/AKT signaling pathway in CRC. |
| Databáze: | OpenAIRE |
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