Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells.
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.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan.
Masanobu
M
Tsubaki
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan.
Tomoya
T
Takeda
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan; Department of Pharmacy, Sakai City Hospital, Sakai, Osaka, Japan.
Naoki
N
Ogawa
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan.
Kotaro
K
Sakamoto
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan.
Hirotaka
H
Shimaoka
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan.
Arisa
A
Fujita
Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara, Japan.
Tatsuki
T
Itoh
Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Motohiro
M
Imano
Department of Pharmacy, Sakai City Hospital, Sakai, Osaka, Japan.
Toshihiko
T
Ishizaka
Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Takao
T
Satou
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashiosaka, Japan. Electronic address: nishida@phar.kindai.ac.jp.
Shozo
S
Nishida
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D014750:Vincristine; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
Drug resistance; Multiple myeloma; Survivin; Vincristine