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

• Published in: Laboratory investigation 2019-01, Vol.99 (1), p.72-84
• Main Authors: Tsubaki, Masanobu, Takeda, Tomoya, Tomonari, Yoshika, Koumoto, Yu-ichi, Imano, Motohiro, Satou, Takao, Nishida, Shozo
• Format: Article
• Language: English
• Subjects: 13/1; 13/89; 13/95; 631/67/1059/2326; 631/67/1990/804; Activation; AKT protein; Antineoplastic Agents, Alkylating; ATP Binding Cassette Transporter, Subfamily B - metabolism; Bcl-2-Like Protein 11 - metabolism; Cell Line; Correlation analysis; Drug Resistance, Neoplasm; Echinomycin; Extracellular signal-regulated kinase; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Inhibitors; Kinases; Laboratory Medicine; Localization; MAP Kinase Signaling System; MDR1 protein; Medicine; Medicine & Public Health; Melphalan; Multidrug resistance; Multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; NF-kappa B - metabolism; NF-κB protein; P-Glycoprotein; Pathology; Phosphorylation; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; siRNA; Survivin; Survivin - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-018-0114-8

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 κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB 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 ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α 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-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM. In this study, the authors show that overexpression of hypoxia-inducible factor(HIF)-1α by ERK1/2, Akt and NF-κB activation contributes to melphalan-resistance in multiple myeloma (MM) cells. Additionally, inhibition of HIF-1α resensitizes melphalan-resistant MM cells to melphalan. Therefore, HIF-1α inhibitors may be therapeutically useful as anti-multidrug resistance protein agents in MM.