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.

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂埃洛替尼与吉西他滨联用已被证明是治疗胰腺癌的一种有前途的疗法。我们以前的研究表明，DJ-1通过激活SRC /细胞外信号调节激酶（ERK）/ uPA促进胰腺癌细胞的侵袭和转移。这项研究的目的是评估DJ-1表达的敲低是否可以使胰腺癌细胞对厄洛替尼治疗敏感。敲低DJ-1表达的加速埃罗替尼诱导的细胞凋亡的和改进的埃罗替尼对胰腺癌细胞增殖的抑制效果（对于的BxPC-3，PANC-1，和的MiaPaCa-2细胞系中，不管KRAS突变状态）体外和体内异种移植肿瘤的生长。击倒DJ-1减少了BxPC-3细胞中的K-RAS表达，膜易位和活性。击倒DJ-1还减少了PANC-1和MiaPACa-2细胞中的K-RAS，H-RAS和N-RAS表达。击倒DJ-1与厄洛替尼在胰腺癌细胞中协同抑制AKT和ERK1 / 2磷酸化。这些发现表明，DJ-1可能会激活RAS通路，从而增强厄洛替尼的耐药性。因此，阻断DJ-1与EGFR酪氨酸激酶抑制剂埃洛替尼的组合可能是胰腺癌中有吸引力的治疗靶标。