Upregulation of IGF2 is associated with an acquired resistance for cis-diamminedichloroplatinum in human head and neck squamous cell carcinoma.

Ten head and neck squamous cell carcinoma (HNSCC) cell lines that had acquired cis-diamminedichloroplatinum (CDDP) resistance were successfully established by means of in vitro culture with CDDP. Flow cytometry analysis showed the significantly decreased induction of apoptosis after the CDDP treatment in the acquired CDDP-resistant sublines. Among these, RPMI2650CR showed a 9.38-fold increased IC50 in comparison with the parental cell line, RPMI2650. The identification of the resistance-related gene clusters was conducted between RPMI2650CR and RPMI2650 using two distinct microarray platforms. The expressional profiles were quite similar, suggesting that a limited number of genes regulate the acquisition of CDDP resistance. IGF2 was found to be one of the candidates for acquired CDDP-resistance. The introduction of IGF2 into RPMI2650 caused CDDP resistance along with suppression of CDDP-dependent apoptosis. On the other hand, siRNA-mediated knockdown of IGF2 caused reduction of acquired CDDP-resistance in RPMI2650CR. These results demonstrate that expression of IGF2 plays an important and critical role in CDDP resistance in a HNSCC cell line RPMI2650. These findings suggest the possibility for developing a new strategy for treating patients with HNSCC, particularly those with acquired CDDP resistance, by combining CDDP with inhibition of the IGF2 pathway.