Pharmacological Inhibition of p38 MAPK by SB203580 Increases Resistance to Carboplatin in A2780cp Cells and Promotes Growth in Primary Ovarian Cancer Cells

Abstract

Chemoresistance renders current chemotherapy regimens ineffective against advanced epithelial ovarian cancer (EOC). Carboplatin (the first-line chemotherapeutic agent to treat EOC) induces cell death by regulating multiple signaling pathways. The objective of this study is to identify the signaling pathways that contribute to carboplatin resistance in EOC. To this end, we performed a proteome profiler human phospho-kinase array experiment and compared the phosphorylation profiles between the cisplatin-sensitive A2780s versus its derivative cisplatin-resistant A2780cp cells. The phospho-kinase array revealed that A2780s and A2780cp cells displayed different profiles in basal and carboplatin-induced phosphorylation. Phosphorylation of p38 MAPK was increased by carboplatin more markedly in A2780s cells compared to A2780cp cells. Inhibition of p38 MAPK activity by its specific inhibitor SB203580 increased resistance to carboplatin in A2780cp cells, but not in A2780s cells or in ascites-derived high-grade serous EOC cells. Interestingly, SB203580 increased the number of viable cells in the primary EOC cells, which was concomitant with an increase in survivin expression. In conclusion, inhibition of p38 MAPK by SB203580 increases resistance to carboplatin in A2780cp cells and the number of viable cells in the primary EOC cells, suggesting that pharmacological inhibition of p38 MAPK might not be an effective therapeutic strategy for EOC.

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…Furthermore, p38 signaling may be involved in antagonizing resistance pathways in cells that are already drug resistant. For instance, p38 inhibition further increased carboplatin resistance in cisplatin-resistant ovarian cancer cells, but not in sensitive cells [140]. The same study showed that p38 inhibition enhanced the viability of primary ovarian cancer cells obtained from ascites, indicating that basic p38 signaling restrains cell survival and its inhibition may be necessary to expand the malignant cell population.…”

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

“… 22 In 2018, a study showed that phosphorylation of p38 mitogen-activated protein kinase (MAPK) was increased by carboplatin more markedly in the cisplatin-sensitive OC cell line A2780s than its derivative cisplatin-resistant A2780cp cells. 23 A 2020 study identified 48 proteins differentially expressed between A2780 and A2780cp; the glycolysis enzyme Enolase-1 (ENO1) was significantly decreased in the cisplatin-resistant OC cells. 24 Most recently, differentially expressed proteins were identified between platinum-resistant OC cell lines (TOV-112D, OVSAHO, and MDAH-2774) and their parental cells, and HSP90 was implicated as a central hub of these protein networks.…”

p38 MAPK Signaling Enhances Reovirus Replication by Facilitating Efficient Virus Entry, Virus Capsid Uncoating and Post-Uncoating Steps

“…P-MKK3/6 increased to a similar extent in anisomycin and p38 MAPK inhibitor treated cells, suggesting that inhibition of p38 MAPK signaling was not due to disruption in the upstream kinase of p38 MAPK. Although p38 MAPK inhibitors SB202190 and SB203580 decreased levels of phospho-p38 following anisomycin treatment, they did not fully eliminate p38 phosphorylation; this is typical among many other studies (19)(20)(21)(22)(23)(24) and caused by continued phosphorylation of p38 MAPK by upstream kinase MKK3/6 (19,20). In other words, the inhibitors bind to the ATP-binding active site of p38 and thereby stop phosphorylation of downstream targets such as MSK and MNK, but do not stop phosphorylation of p38 by upstream MKKs.…”