Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Department of Clinical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Cell Death Dis. 2020 Oct 22;11(10):898. doi: 10.1038/s41419-020-03107-3.
Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276, P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.
目前，只有少数几种靶向药物被认为对胃腺癌（STAD）治疗有效。PARP 抑制剂奥拉帕利是一种针对特定分子的药物，在 BRCA 突变肿瘤中仍在进行研究。然而，在没有 BRCA 基因突变的肿瘤中，特别是在 STAD 中，奥拉帕利的作用和分子机制尚不清楚，这在很大程度上限制了奥拉帕利在 STAD 治疗中的应用。在这项研究中，体外结果表明，奥拉帕利特异性抑制 STAD 细胞系的细胞生长和迁移，发挥抗肿瘤作用。此外，在 STAD 细胞中鉴定并验证了 ClC-3/SGK1 调节轴。然后发现，下调 ClC-3/SGK1 轴可减弱奥拉帕利诱导的细胞生长和迁移抑制。相反，上调 ClC-3/SGK1 轴增强了奥拉帕利诱导的细胞生长和迁移抑制，而 SGK1 敲低可减弱增强作用。同样，奥拉帕利激活的全细胞氯离子电流也呈现出相同的变化趋势。接下来，临床数据显示，ClC-3 和 SGK1 在人类 STAD 组织中高表达且呈正相关（r=0.276，P=0.009）。此外，ClC-3（P=0.030）和 SGK1（P=0.006）的高蛋白表达与 STAD 患者的生存率差相关，通过 GEPIA 数据集证明了 STAD 组织中 ClC-3/SGK1 及其下游分子之间的正相关关系。最后，我们的结果表明，奥拉帕利抑制了 STAD 细胞中的 PI3K/AKT 通路，上调 ClC-3/SGK1 轴增强了奥拉帕利诱导的 PI3K/AKT 通路抑制。动物实验表明，奥拉帕利在体内也具有抗肿瘤作用。总的来说，我们的研究结果表明，奥拉帕利在人类 STAD 中发挥抗肿瘤作用，ClC-3/SGK1 调节轴增强了奥拉帕利诱导的抗肿瘤作用。上调 ClC-3/SGK1 轴可能为奥拉帕利在 STAD 治疗中的临床应用提供有前景的治疗潜力。
