Abstract

BackgroundWe investigated the role of the ETS-1 transcription factor in Head and Neck Squamous Cell Carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines.MethodsWe examined its molecular link with SRC and MEK/ERK pathways and determined the efficacy of either MEK/ERK inhibitor PD0325901 or SRC inhibitor Dasatinib on cisplatin-resistant HNSCC inhibition.ResultsWe found that ETS-1 protein expression levels in a majority of cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin sensitive partners. High ETS-1 expression was also found in patient-derived, cisplatin-resistant HNSCC cells. While ETS-1 knockdown inhibited cell proliferation, migration, and invasion, it could still re-sensitize cells to cisplatin treatment. Interestingly, previous studies have shown that MER/ERK pathways could regulate ETS-1 through its phosphorylation at threonine 38 (T38). Although almost all cisplatin-resistant HNSCC cells we tested showed higher ETS-1 phosphorylation levels at T38, we found that inhibition of MEK/ERK pathways with the MEK inhibitor PD0325901 did not block this phosphorylation. In addition, treatment of cisplatin-resistant HNSCC cells with the MEK inhibitor completely blocked ERK phosphorylation but did not re-sensitize cells to cisplatin treatment. Furthermore, we found that, consistent with ETS-1 increase, SRC phosphorylation dramatically increased in cisplatin-resistant HNSCC, and treatment of cells with the SRC inhibitor, Dasatinib, blocked SRC phosphorylation and decreased ETS-1 expression. Importantly, we showed that Dasatinib, as a single agent, significantly suppressed cell proliferation, migration, and invasion, in addition to survival.ConclusionsOur results demonstrate that the SRC/ETS-1 pathway plays a crucial role and could be a key therapeutic target in cisplatin-resistant HNSCC treatment.

Highlights

  • We investigated the role of the ETS-1 transcription factor in Head and Neck Squamous Cell Carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines

  • In order to identify the crucial oncogenic and survival proteins and signaling pathways associated with HNSCC recurrence and metastasis, development of agents to counteract cisplatin resistance remains a major focus in HNSCC research

  • ETS-1 is up-regulated in a majority of cisplatin-resistant HNSCC We previously reported two pairs of cisplatin-sensitive/ resistant HNSCC cells: SCC25/ SCC25CP cells and UMSCC17B/UMSCC17B-CP cells [16]

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Summary

Introduction

We investigated the role of the ETS-1 transcription factor in Head and Neck Squamous Cell Carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines. Cisplatin-containing chemotherapy is the first option to treat recurrent and metastatic HNSCC This treatment only achieves a good response for a short time because a majority of patients develop resistance to cisplatin and will die within one year [1,2,3,4]. The ETS-1 transcription factor is a 54 kDa nuclear protein that functions as a transcriptional activator It plays a role in cancer progression through a number of processes, which include regulation of proliferation, invasion, epithelial-to-mesenchymal transition (EMT), metabolism, angiogenesis, and drug resistance in many types of cancers [5]. It has been reported that ETS-1 plays an important role in promoting tumor invasion in

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