Significance of ATP-binding cassette transporter proteins in multidrug resistance of head and neck squamous cell carcinoma.

ABSTRACT

According to the cancer stem cell theory, a small subpopulation of cancer cells, known as cancer stem cells (CSCs), exist that are self-renewing and are involved in tumor invasion, metastasis and recurrence. A number of studies have reported that certain cancer cells are able to efflux the Hoechst 33342 dye. These cells are termed side population (SP) cells and share characteristic features of CSCs. The results of the present study revealed that 2.7% of primary head and neck squamous cell carcinoma (HNSCC) cells were SP cells. This was reduced to 0.7% following treatment with verapamil. The immunofluorescence and reverse transcription polymerase chain reaction analysis revealed that SP cells have an enhanced expression of the ATP-binding cassette (ABC) transporter protein ABC subfamily G, member 2 (ABCG2), which has been identified to be actively involved in drug exclusion. Similarly, the mRNA level of the oncogene B lymphoma Mo-MLV insertion region-1 and the stem cell surface proteins nestin and octamer-binding transcription factor-4 were highly expressed in the SP cells compared with the non-SP cells. In addition, it was demonstrated that HNSCC SP cells exhibited increased proliferation and were highly resistant to multiple drugs. These findings suggest that the presence of CSCs, such as SP cells, may be responsible for chemotherapy failure and tumor relapse in patients with HNSCC. Therefore, the identification of a novel therapeutic drug that could effectively target CSCs may help to eradicate refractory tumors.