Savino Luca, Di Marcantonio Maria Carmela, Moscatello Carmelo, Cotellese Roberto, Centurione Lucia, Muraro Raffaella, Aceto Gitana Maria, Mincione Gabriella
Department of Innovative Technologies in Medicine and Dentistry, University 'G. d'Annunzio' of Chieti-Pescara, Chieti, Italy.
Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio' of Chieti-Pescara, Chieti, Italy.
Front Oncol. 2022 Mar 16;12:860760. doi: 10.3389/fonc.2022.860760. eCollection 2022.
Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with HO alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with HO combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after HO treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed and increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration a different modulation of PI3K and MAPKs pathways. Moreover, the observed and induction is a cellular response to protect the cells from HO-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used.
在全球范围内，胃癌的发病率和死亡率分别位居第五和第三。胃壁每天都暴露于氧化应激之下，碱基切除修复（BER）系统在抵御氧化诱导的DNA损伤中起关键作用，而表皮生长因子受体（ErbB）在癌症发病机制中具有重要作用。我们使用AGS细胞作为侵袭性胃癌细胞模型，单独用羟基脲（HO）或与ErbB信号通路抑制剂联合处理，以评估氧化应激在胃癌中的作用，重点关注ErbB信号通路的调节及其与BER系统的最终相互作用。我们发现，HO与磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT）和丝裂原活化蛋白激酶（MEK）抑制剂联合处理会影响细胞形态，并导致癌细胞活力降低。单独使用HO或与MEK抑制剂联合处理以及单独使用PI3K/AKT抑制剂后，迁移能力均降低。蛋白质印迹分析表明，氧化应激刺激表皮生长因子受体（EGFR）通路，以PI3K/AKT通路为代价促进丝裂原活化蛋白激酶（MAPKs）的激活。逆转录定量聚合酶链反应（RT-qPCR）基因表达分析表明，在氧化应激条件下，[具体基因]和[具体基因]表达增加。因此，我们认为在AGS细胞中，促氧化处理可通过对PI3K和丝裂原活化蛋白激酶（MAPKs）通路的不同调节来降低胃癌细胞的生长和迁移。此外，观察到的[具体基因]和[具体基因]的诱导是细胞对羟基脲诱导的细胞死亡的一种保护反应。总之，为了定制特定的联合治疗方案并决定使用哪种策略，给予一种能将细胞内活性氧增加到有毒水平的化疗药物，可能不仅取决于肿瘤类型，还取决于所使用的分子靶向治疗。
