Title The role and efficacy of JNK inhibition in inducing lung cancer cell death depend on the concentration of cisplatin /
Authors Stulpinas, Aurimas ; Tenkutytė, Monika ; Imbrasaitė, Aušra ; Kalvelytė, Audronė Valerija
DOI 10.1021/acsomega.4c01950
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Is Part of ACS Omega.. Washington : American Chemical Society (ACS). 2024, vol. 9, iss. 26, p. 28311-28322.. ISSN 2470-1343. eISSN 2470-1343
Abstract [eng] 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.
Published Washington : American Chemical Society (ACS)
Type Journal article
Language English
Publication date 2024
CC license CC license description