Abstract

Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

中文翻译：

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DJ-1通过PTEN / PI3K / Akt / Nrf2途径参与SGC7901胃癌细胞的多药耐药性

摘要

胃癌是全世界常见的恶性肿瘤。多药耐药（MDR）的发生是有效的胃癌化学疗法的主要障碍。在这项研究中，深入研究了DJ-1诱导的SDR在SGC7901胃癌细胞中的分子机制。结果表明，MDR变异SGC7901 / VCR细胞中DJ-1表达水平高于其亲本SGC7901细胞。此外，DJ-1的过表达赋予SGC7901细胞MDR表型，而SGC7901 / VCR细胞中的DJ-1敲低则引起对阿霉素，长春新碱，顺铂和5-氟尿嘧啶的再敏化。这些结果表明DJ-1介导SGC7901胃癌细胞中MDR的发展。重要的，进一步的数据表明，PI3k / Akt和Nrf2信号通路的激活是SGC7901胃癌细胞中DJ-1诱导的MDR表型所必需的。同时，我们发现PI3k / Akt途径可能是通过DJ-1直接与PTEN结合并对其负调控而激活的，从而导致Nrf2磷酸化和激活，从而诱导Nrf2依赖性P-糖蛋白（P-gp）和Bcl-2 SGC7901胃癌细胞在DJ-1介导的MDR中的表达 总体而言，这些结果表明，激活PTEN / PI3K / Akt / Nrf2途径并随后上调P-gp和Bcl-2表达可能是DJ-1介导SGC7901胃癌细胞中MDR发育的关键机制。新发现可能有助于了解胃癌细胞中MDR的机制，