The relationship between p38MAPK and apoptosis during paclitaxel resistance of ovarian cancer cells

Abstract

To investigate the relationship between p38 mitogen-activated protein kinase (p38MAPK) and cell apoptosis during the paclitaxel resistance of ovarian carcinoma cell lines, flow cytometry (FCM) and PI staining were employed to determine the effect of p38MAPK inhibitor SB203580 on the apoptosis of A2780/Taxol cells, a drug-resistant human ovarian carcinoma cell line. p38MAPK protein expression in SB203580-treated cells was immunochemically measured. The 50% inhibition concentration (IC₅₀) of paclitaxel on A2780/Taxol cells was determined by MTT assay. MDR-1 mRNA, and expression of p38MAPK and phospho-p53 protein were detected by RT-PCR and Western blotting, respectively. The apoptosis rate of A2780/Taxol cells was (19.7±1.04)% 24 h after SB203580 treatment. A significant difference in apoptosis rate was found among experiment group, control group and untreated group (P<0.05). The relative reversal rate of A2780/Taxol cells to paclitaxel was (57.18±2.01)%. As compared with the control group and the untreated group, p38MAPK protein and MDR-1 mRNA in SB203580-treated cells was substantially decreased. The expression of p53 protein was significantly increased. It is concluded that p38MAPK pathway is related to paclitaxel resistance of ovarian carcinoma, and blockade of this pathway can promote the apoptosis of the drug-resistant cells and reverse the drug-resistance. Moreover, p38MAPK-mediated apoptosis in paclitaxel-resistant ovarian carcinoma cells depends on the activation of p53.

Keywords

ovarian carcinoma / cell apoptosis / p38 mitogen-activated protein kinase / multidrug resistance

References

[1] ParkM. T., ChoiJ. A., KimM. J., et al.. Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8 and mitochondriamediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem, 2003, 278: 50624-50634

[2] FesikS. W.. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer, 2005, 5(11): 876-885

[3] XiongH. Q.. Molecular targeting therapy for pancreatic cancer. Cancer Chemother Pharmacol, 2004, 54(Suppl1): S69

[4] EnglishJ. M., CobbM. H.. Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci, 2002, 23(1): 40-45

[5] LinJ. C., ChangS. Y., HsiehD. S., et al.. Modulation of mitogen-activated protein kinase cascades by differentiation-1 protein: acquired drug resistance of hormone independent prostate cancer cells. J Urol, 2005, 174(5): 2022-2026

[6] WadaT., PenningerJ. M.. Mitogen-activated protein kinases in apoptosis regulation. Oncogene, 2004, 23(16): 2838-2849

[7] DentP., YacoubA., FisherP. B., et al.. MAPK pathways in radiation responses. Oncogene, 2003, 22(37): 5885-5896

[8] HabiroA., TannoS., KoizumiK., et al.. Involvement of p38 mitogen-activated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells. Biochem Biophys Res Commun, 2004, 316: 71-78

[9] RicardoS. P., JoseM. R., YoichiJ., et al.. A role for the p38 mitogen-activated protein kinase pathway in the transcriptional activation of p53 on gerlotoxic stress by chemotherapeutic agents. Cancer Res, 2000, 60: 2464-2472

[10] KohnoM., PouyssegurJ.. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog Cell Cycle Res, 2003, 5: 219-2248