Stulpinas Aurimas, Tenkutytė Monika, Imbrasaitė Aušra, Kalvelytė Audronė V
Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius 10257, Lithuania.
ACS Omega. 2024 Jun 18;9(26):28311-28322. doi: 10.1021/acsomega.4c01950. eCollection 2024 Jul 2.
Toxicity and the emergence of resistance are the main challenges in cancer treatment. The optimal dose of cisplatin, one of the most widely used chemotherapeutic anticancer drugs, is currently being widely debated. Furthermore, the dose-dependent molecular mechanisms of its action are poorly understood. To assess the role of protein kinase JNK (cJun N-terminal kinase) signaling in lung cancer treatment, we combined small-molecule JNK inhibitors and cisplatin. Wild-type p53 (tumor suppressor transcription factor TP53) and mutated RAS-bearing lung adenocarcinoma cell line A549 was used as a model in our studies. Here, we demonstrate cisplatin concentration-dependent opposing roles of JNK in killing cancer cells: a cell-protective role at low cisplatin concentrations and an apoptosis-promoting (or neutral) role at high concentrations. Time- and dose-dependent activation of pro-survival protein kinase AKT and TP53 was shown, with similar activation dynamics in cells exposed to different (low and high) cisplatin concentrations. Selective inhibition of AKT and activation of TP53 (expression and phosphorylation) led to a decrease in cell survival, indicating their involvement in cisplatin-induced cell death regulation. The activation levels of TP53 and AKT in cisplatin-treated A549 cells after cotreatment with the JNK inhibitor SP600125 correlated with their role in regulating cell death. TP53 and AKT were proposed as signaling proteins mediating the outcome of JNK inhibition in A549 cells exposed to different concentrations of cisplatin. Our findings suggest that a combination of stress kinase JNK inhibition and low-dose cisplatin, together with manipulation of drug-induced signaling, could be considered as a promising treatment strategy for certain lung cancers.
毒性和耐药性的出现是癌症治疗中的主要挑战。顺铂是使用最广泛的化疗抗癌药物之一，其最佳剂量目前正受到广泛争议。此外，其作用的剂量依赖性分子机制尚不清楚。为了评估蛋白激酶JNK（cJun氨基末端激酶）信号通路在肺癌治疗中的作用，我们将小分子JNK抑制剂与顺铂联合使用。在我们的研究中，使用野生型p53（肿瘤抑制转录因子TP53）和携带突变RAS的肺腺癌细胞系A549作为模型。在这里，我们证明了JNK在杀死癌细胞方面具有顺铂浓度依赖性的相反作用：在低顺铂浓度下具有细胞保护作用，在高浓度下具有促凋亡（或中性）作用。研究表明，促生存蛋白激酶AKT和TP53存在时间和剂量依赖性激活，在暴露于不同（低和高）顺铂浓度的细胞中具有相似的激活动力学。选择性抑制AKT并激活TP53（表达和磷酸化）导致细胞存活率降低，表明它们参与顺铂诱导的细胞死亡调节。在用JNK抑制剂SP600125共同处理后，顺铂处理的A549细胞中TP53和AKT的激活水平与其在调节细胞死亡中的作用相关。TP53和AKT被认为是介导JNK抑制对暴露于不同浓度顺铂的A549细胞影响的信号蛋白。我们的研究结果表明，抑制应激激酶JNK和低剂量顺铂联合使用，再加上对药物诱导信号通路的调控，可能是某些肺癌有前景的治疗策略。
