Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

Abstract

The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

Up-Regulation of Extracellular Signal-Regulated Kinase 1/2-Dependent Thymidylate Synthase and Thymidine Phosphorylase Contributes to Cisplatin Resistance in Human Non–Small-Cell Lung Cancer Cells

“…In A549 lung carcinoma cells, targeting ATF3 with specific siRNA also attenuated the cytotoxic effects of cisplatin. Likewise, ATF3(Ϫ/Ϫ) MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3(ϩ/ϩ) MEFs (St Germain et al, 2010). In this present study, we first demonstrated that cisplatin could induce TS and TP expression through the activation of ERK1/2.…”

miR-483-5p determines mitochondrial fission and cisplatin sensitivity in tongue squamous cell carcinoma by targeting FIS1

“…Notably, it is unclear how miR-483-5p can be downregulated by cisplatin. Previous studies have demonstrated that cisplatin could induced transcriptomics responses, such as the changes in the expression of HNF4-α, SP1, c-MYC, TP53 [31] and ATF3 [32]. Moreover, alterations in gene promoter methylation have also been found by cisplatin treatment [33].…”

Ectopic Expression of Human MutS Homologue 2 on Renal Carcinoma Cells Is Induced by Oxidative Stress with Interleukin-18 Promotion via p38 Mitogen-activated Protein Kinase (MAPK) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

“…The synthesis of ATF3, a member of the AP-1 subfamily activating transcription factors, is quite robust relative to the levels of other oxidative stress-induced AP-1 proteins (42). We found that transcription factor binding sites for the AP-1 family presenting in the regulatory element of hMSH2 were matched to ATF3 transcription factor binding sites (43)(44)(45): AP-1, Ϫ611 to Ϫ605 (5Ј-TGAATCA-3Ј) and Ϫ297 to Ϫ291 (5Ј-TGAGTAA-3Ј); ATF/cAMP-response element, Ϫ1156 to Ϫ1149 (5Ј-TGACGTCA-3Ј). Therefore, we tested if ATF3 is involved in the regulation of ectopic expression of hMSH2 during oxidative stress.…”