Knockdown of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition
| Autor: | Rong Fan, Xiangyi He, Jing Sun, Yunwei Sun, Douwu Zou, Yaozong Yuan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research DJ-1 erlotinib endocrine system diseases medicine.drug_class pancreatic cancer lcsh:RC254-282 Tyrosine-kinase inhibitor Metastasis 03 medical and health sciences 0302 clinical medicine Pancreatic cancer medicine Pharmacology (medical) Epidermal growth factor receptor Protein kinase B neoplasms Gene knockdown biology ERK1/2 Chemistry AKT medicine.disease sensitivity lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens respiratory tract diseases 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Erlotinib Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 20, Iss, Pp 364-372 (2021) |
| ISSN: | 2372-7705 |
| Popis: | The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, in combination with gemcitabine, has been shown to be a promising therapy in the treatment of pancreatic cancer. Our previous study showed that DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/extracellular signal-regulated kinase (ERK)/uPA. The aim of this study was to evaluate whether knockdown of DJ-1 expression can sensitize pancreatic cancer cells to erlotinib treatment. Knockdown of DJ-1 expression accelerated erlotinib-induced cell apoptosis and improved the inhibitory effect of erlotinib on pancreatic cancer cell proliferation (for the BxPC-3, PANC-1, and MiaPACa-2 cell lines, regardless of KRAS mutation status) in vitro and in xenograft tumor growth in vivo. Knockdown of DJ-1 decreased K-RAS expression, membrane translocation, and activity in BxPC-3 cells. Knockdown of DJ-1 also decreased K-RAS, H-RAS, and N-RAS expression in PANC-1 and MiaPACa-2 cells. Knockdown of DJ-1 synergistically inhibited AKT and ERK1/2 phosphorylation with erlotinib in pancreatic cancer cells. These findings indicate that DJ-1 may activate the RAS pathway, reinforcing erlotinib drug resistance. Therefore, blocking DJ-1 in combination with the EGFR tyrosine kinase inhibitor erlotinib may be an attractive therapeutic target in pancreatic cancer. |
| Databáze: | OpenAIRE |
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