The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, China.
Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
Acta Biochim Biophys Sin (Shanghai). 2020 Dec 11;52(11):1202-1214. doi: 10.1093/abbs/gmaa110.
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.
胃癌是一种常见的恶性肿瘤。多药耐药（MDR）的发生是胃癌化疗有效治疗的主要障碍。在这项研究中，深入研究了 DJ-1 诱导 SGC7901 胃癌细胞 MDR 的分子机制。结果表明，MDR 变体 SGC7901/VCR 细胞中的 DJ-1 表达水平高于其亲本 SGC7901 细胞。此外，DJ-1 过表达赋予 SGC7901 细胞 MDR 表型，而 SGC7901/VCR 细胞中 DJ-1 的敲低诱导对阿霉素、长春新碱、顺铂和 5-氟尿嘧啶的重新敏感。这些结果表明 DJ-1 介导了 SGC7901 胃癌细胞 MDR 的发展。重要的是，进一步的数据表明，PI3k/Akt 和 Nrf2 信号通路的激活是 DJ-1 诱导 SGC7901 胃癌细胞 MDR 表型所必需的。同时，我们发现 PI3k/Akt 通路可能通过 DJ-1 直接与 PTEN 结合并负调控其活性，导致 Nrf2 磷酸化和激活，从而诱导 DJ-1 介导的 SGC7901 胃癌细胞 MDR 中 Nrf2 依赖性 P-糖蛋白（P-gp）和 Bcl-2 的表达。总的来说，这些结果表明激活 PTEN/PI3K/Akt/Nrf2 通路，随后上调 P-gp 和 Bcl-2 的表达可能是 DJ-1 介导 SGC7901 胃癌细胞 MDR 发展的关键机制。新发现可能有助于理解胃癌细胞 MDR 的机制，促使进一步研究将其作为克服 MDR 的分子靶点。
