期刊
MOLECULAR THERAPY-ONCOLYTICS
卷 20, 期 -, 页码 364-372出版社
CELL PRESS
DOI: 10.1016/j.omto.2021.01.013
关键词
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资金
- National Natural Science Foundation of China [81672448]
- Natural Science Foundation of Shanghai [19ZR1432000]
- Guangci Excellent Youth Program A of Ruijin Hospital [GCQN-2017-A01]
Knockdown of DJ-1 expression sensitizes pancreatic cancer cells to erlotinib treatment by accelerating apoptosis and inhibiting proliferation, while also affecting RAS pathway activation and AKT/ERK1/2 phosphorylation. Blocking DJ-1 in combination with erlotinib may be a potential therapeutic strategy in pancreatic cancer.
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.
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