Purpose Head and neck squamous cell carcinoma (HNSCC) cell lines with cytoplasmically sequestered mutant p53 (p53mut_c) are frequently more resistant to cisplatin (CDDP) than cells with mutant but nuclear p53 (p53mut_n). The aim of the study was to identify underlying mechanisms implicated in CDDP resistance of HNSCC cells carrying cytoplasmic p53mut.

Methods Microarray analysis, quantitative reverse transcription polymerase chain reaction, Western blot analysis and immunocytochemistry were used to identify and evaluate candidate genes involved in CDDP resistance of p53mut_c cells. RNA i knockdown or treatment with inhibitors together with flow cytometry-based methods was used for functional assessment of the identified candidate genes. Cellular metabolic activity was assessed with the XTT assay, and the redox capacity of cells was evaluated by measuring cellular glutathione (GSH) levels.

Results Upregulation of ABCC2 and ABCG2 transporters was observed in CDDP-resistant p53mut_c HNSCC cells. Furthermore, p53mut_c cells exhibited a pronounced side population that could be suppressed by RNA i knockdown of ABCG2 as well as treatment with the AT P-binding-cassette transporter inhibitors imatinib, MK571 and tariquidar. Metabolic activity and cellular GSH levels were higher in CDDP-resistant p53mut_c cells, consistent with a higher capacity to fend off cytotoxic oxidative effects such as those caused by CDDP treatment. Finally, ABCC2/G2 inhibition of HNSCC cells with MK571 markedly enhanced CDDP sensitivity of HNSCC cells.