Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells.

Abstract

The acquisition of anti-cancer drug resistance is a major limitation of chemotherapy for multiple myeloma (MM) and it is thus important to identify the mechanisms by which MM cells develop such drug resistance. In a previous study, we showed that multidrug resistance (MDR) involves the overexpression of MDR1 and survivin in vincristine-resistant RPMI8226/VCR cells. However, the underlying mechanism of MDR remains unclear. In this study, we investigated the mechanism of MDR in RPMI8226/VCR cells, and found that RPMI8226/VCR cells exhibit increased levels of activated ERK1/2, Akt, and NF-κB, while the levels of activated mTOR, p38MAPK, and JNK do not differ between RPMI8226/VCR cells and their vincristine-susceptible counterparts. In addition, the inhibition of ERK1/2, Akt, or NF-κB by inhibitors reversed the drug-resistance of RPMI8226/VCR cells via the suppression of survivin expression, but did not affect MDR1 expression; RNA silencing of survivin expression completely reversed vincristine resistance, while MDR1 silencing only weakly suppressed vincristine resistance in RPMI8226/VCR cells. These results indicate that enhanced survivin expression via the activation of ERK1/2, Akt, and NF-κB plays a critical role in vincristine resistance in RPMI8226/VCR cells. Our findings suggest that ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of vincristine-resistant MM.

• Authors: Masanobu Tsubaki, Tomoya Takeda, Naoki Ogawa, Kotaro Sakamoto, Hirotaka Shimaoka, Arisa Fujita, Tatsuki Itoh, Motohiro Imano, Toshihiko Ishizaka, Takao Satou, Shozo Nishida
• Journal: Leukemia research (Leuk Res) Vol. 39 Issue 4 Pg. 445-52 (Apr 2015) ISSN: 1873-5835 [Electronic] England
• PMID: 25726084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• NF-kappa B
• RNA, Messenger
• RNA, Small Interfering
• Survivin
• Vincristine
• Proto-Oncogene Proteins c-akt
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis
• Blotting, Western
• Cell Proliferation
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Inhibitor of Apoptosis Proteins (antagonists & inhibitors, genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Multiple Myeloma (drug therapy, metabolism, pathology)
• NF-kappa B (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survivin
• Tumor Cells, Cultured
• Vincristine (pharmacology)