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.
Keywords:
Drug resistance; Multiple myeloma; Survivin; Vincristine.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
Antineoplastic Agents, Phytogenic / pharmacology
-
Apoptosis
-
Blotting, Western
-
Cell Proliferation
-
Drug Resistance, Multiple*
-
Drug Resistance, Neoplasm*
-
Humans
-
Inhibitor of Apoptosis Proteins / antagonists & inhibitors
-
Inhibitor of Apoptosis Proteins / genetics
-
Inhibitor of Apoptosis Proteins / metabolism*
-
Mitogen-Activated Protein Kinase 1 / genetics
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Multiple Myeloma / drug therapy*
-
Multiple Myeloma / metabolism
-
Multiple Myeloma / pathology*
-
NF-kappa B / genetics
-
NF-kappa B / metabolism
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism
-
RNA, Messenger / genetics
-
RNA, Small Interfering / genetics
-
Real-Time Polymerase Chain Reaction
-
Reverse Transcriptase Polymerase Chain Reaction
-
Survivin
-
Tumor Cells, Cultured
-
Vincristine / pharmacology*
Substances
-
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