Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor.B (NF-kappa B). The combination of ERK1/2, Akt, and NF-kappa B inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH77/ L-PAM cells overexpressed hypoxia-inducible factor 1 alpha (HIF-1 alpha) via activation of ERK1/2, Akt, and NF-kappa B. Moreover, suppression of HIF-1 alpha by echinomycin or HIF-1 alpha siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1 alpha via activation of ERK1/2, Akt, and NF-kappa B play a critical role in melphalan resistance. Our findings suggest that HIF-1 alpha, ERK1/2, Akt, and NF-kappa B inhibitors are potentially useful as antiMDR agents for the treatment of melphalan-resistant MM.