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

Xiaolu Han,Helen Steed,Lynne-Marie Postovit,Jiesi Zhou,Huachen Chen,Yangxin Fu

doi:10.3390/ijms19082184

Xiaolu Han, Helen Steed + Show 4 more

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https://doi.org/10.3390/ijms19082184

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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.

Highlights

Epithelial ovarian cancer (EOC) comprises approximately 90% of ovarian cancer, the most lethal gynecologic malignancy worldwide [1]
Our previous study determined that cisplatin-resistant A2780cp cells are more resistant to carboplatin when compared to A2780s cells [27]
Because published studies showed that p38 mitogen-activated protein kinase (MAPK) mediates survivin downregulation and apoptosis induced by tanshinone IIA and a high dose of nitric oxide in EOC cells [21,35,36], we examined how carboplatin and SB203580 treatment affects survivin expression in the primary EOC cells

Summary

Introduction

Epithelial ovarian cancer (EOC) comprises approximately 90% of ovarian cancer, the most lethal gynecologic malignancy worldwide [1]. High-grade serous EOC is the most common and lethal histological subtype, accounting for approximately 75% of all EOC cases [2]. Most EOC cases are diagnosed at advanced stages and require a combination of surgery and chemotherapy (carboplatin in combination with paclitaxel being the first-line treatment). Despite the initial positive response to chemotherapy, most EOCs relapse and develop chemoresistance, rendering current therapeutic regimens ineffective against advanced EOC. The current 5-year survival rate for advanced EOC is about 30% [3].

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