The extracellular signal-regulated kinases (ERKs) are key transducers of the extracellular signals into intracellular responses and represent major molecular players in tumorigenesis. The aim of this study was to determine how curcumin (CRM) used as an adjuvant supports the apoptotic process induced by a single chemical agent treatment (cisplatin-CisPT) on two head and neck squamous cell carcinoma cell lines (FaDu and PE/CA-PJ49) and the involvement of ERK1/2 and/or p53 activation in this process. Data have shown that the CisPt effect is potentiated by CRM. CRM induced an increase of p53 protein phosphorylation in both cell lines. CisPt decreased p53 protein phosphorylation in FaDu cells, but increased it in PE/CA-PJ49 cells. Data showed that the constitutive expression of activated ERK1/2 protein-kinase was different in the two analyzed tumor cell lines. ERK1/2 activation status was essential for both cell processes, proliferation and apoptosis induced by CisPt and/or CRM treatment on squamous cell carcinoma cells. Our data suggest that p53 phosphorylation in the apoptotic process induced by CRM treatment might require the involvement of ERK1/2. In this regard the CisPt treatment suggested that p53 phosphorylation is ERK1/2 independent in FaDu cells having a p53 gene deletion and ERK1/2 dependent in PE/CA-PJ49 cells having a p53 gene amplification. Moreover, in both tumor cell lines our results support the involvement of p53 phosphorylation-ERK1/2 activation-dependent in the apoptosis induced by combined treatments (CisPt and CRM). The use of CRM as adjuvant could increase the efficiency of chemotherapy by modulating cellular activation processes of ERK1/2 signaling pathways. In conclusion, the particular mode of intervention by which ERK1/2 might influence cell proliferation and/or apoptosis processes depends on the type of therapeutic agent, the cells' particularities, and the activation status of the ERK1/2.

Natural compounds can modulate all three major phases of carcinogenesis. The role of the natural compounds such as resveratrol (RSV) and curcumin (CRM) in modulation of anticancer potential of platinum-based drugs (CisPt) is still a topic of considerable debate. In order to enhance head and neck cancer (HNSCC) cells’ sensitivity to the cytotoxic effects of CisPt combined treatments with RSV or CRM were used. The study aim was to evaluate how the RSV or CRM associated to CisPt treatment modulated some cellular processes such as proliferation, P21 gene expression, apoptotic process, and cell cycle development in HNSCC tumor cell line (PE/CA-PJ49) compared to a normal cell line (HUVEC). The results showed that RSV or CRM treatment affected the viability of tumor cells more than normal cells. These natural compounds act against proliferation and sustain the effects of cisplatin by cell cycle arrest, induction of apoptosis and amplification of P21 expression in tumor cells. In conclusion, using RSV or CRM as adjuvants in CisPt therapy might have a beneficial effect by supporting the effects induced by CisPt.

In head and neck cancers, the effectiveness of cisplatin (CisPt) treatment is limited by its toxicity, especially when higher doses are necessary, and the possible occurrence of cisplatin resistance. This study evaluated the effects of resveratrol (RSV) on the expression of different genes involved in the response of human tumor cells (FaDu, PE/CA-PJ49) to cisplatin therapy. Our results revealed that RSV induced apoptosis amplification in both FaDu and PE/CA-PJ49 cells and modulated the expression of specific genes differently than in normal HaCaT cells. In FaDu cells, combined CisPt + RSV treatment induced an increase in apoptosis, which was associated with an increase in c-MYC and TP53 and a decrease in BCL-2 expression. While CisPt + RSV treatment induced apoptosis in PE/CA-PJ49 cells by inhibition of BCL-2 associated with high levels of MDM-2 and subsequently led to inhibition of TP53 gene expression. Decreased c-MYC expression in PE/CA-PJ49 treated with CisPt + RSV was accompanied by cell cycle blockage in G0/G1 phase. In conclusion, RSV influences tumor cell response to CisPt by inducing apoptosis and modulating gene expression. In addition, in normal HaCaT cells, RSV was able to reduce the harmful effects of CisPt.

To cite this article: PETRICA-MATEI GG, ROMAN V, MIHAILA M. HOTNOG CM, BRASOVEANU LI, BOSTAN M. Role of p38-mitogen-activated protein kinase in modulation of the response to therapy in FaDu Human pharyngeal carcinoma cell. AbstractAlthough cisplatin (CisPt) is used in treating head and neck squamous cell carcinomas (HNSCC), little is known about the cellular mechanisms triggered. We examined the morphological and functional changes in HNSCC cells when natural compounds such as resveratrol (RSV) are added to CisPt treatment of FaDu human pharyngeal carcinoma cell line. In addition, we analyzed the effects of CisPt and/or RSV treatments on cell proliferation and evaluated the ability to modulate the activation of p38 Mitogen-Activated Protein Kinase (p38MAPK). Moreover, we explored whether activation of p38MAPK is associated with p53 phosphorylation status in FaDu cells using SB203580 specific p38MAPK inhibitor. Proliferation vs. cytotoxicity induced by CisPt and/or RSV treatments in FaDu cells were studied using MTS colorimetric assay and evaluating cell viability. Whereas the activation of p38MAPK could be specific to HNSCC therapy, we investigated the phosphorylation status of p38 and p53 proteins by ELISA assays, using antibodies that recognize their dual forms (the active, phosphorylated and the total one). The obtained data showed that RSV enhanced the cytotoxic effect of CisPt in FaDu cells, having a synergic effect and the ability to promote p53 phosphorylation, suggesting a possible link between the p38MAPK and p53 activation pathways.

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