Involvement of thioredoxin-binding protein 2 in the antitumor activity of CD437.
The present authors previously reported that a synthetic retinoid, CD437, induces endoplasmic reticulum stress-mediated apoptosis in ovarian adenocarcinoma cells in spite of no response to natural retinoids. However, the precise mechanism of its proapoptotic action has not been fully determined. The present study herein demonstrates that apoptosis induction of ovarian adenocarcinoma SKOV3 cells by CD437 involves the upregulation of thioredoxin-binding protein 2 (TBP2) by a mechanism that is dependent on the intracellular calcium concentration. TBP2 is known to bind to and suppress thioredoxin (TRX) activity whereas TRX has an anti-apoptotic effect by inhibiting apoptosis signal-regulating kinase 1 (ASK1). The activation of ASK1 and its downstream molecule, c-Jun N-terminal kinase, was observed after induction of TBP2 by CD437. Interestingly, CD437 induced the association of TBP2 with TRX and, in turn, facilitated the dissociation of ASK1 from TRX. Moreover, blockade of TBP2 induction by small interfering RNA (siRNA) significantly attenuated the cytotoxic effect of CD437. These results suggest that TBP2 plays a critical role in the mechanism by which CD437 exerts proapoptotic action against SKOV3 cells.
Matsuoka
Saori
S
Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Nishi-cho 86, Yonago, Tottori 683-8504, Japan.
Tsuchiya
Hiroyuki
H
Sakabe
Tomohiko
T
Watanabe
Yumi
Y
Hoshikawa
Yoshiko
Y
Kurimasa
Akihiro
A
Itamochi
Hiroaki
H
Harada
Tasuku
T
Terakawa
Naoki
N
Masutani
Hiroshi
H
Yodoi
Junji
J
Shiota
Goshi
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024161:Collagen Type XI / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D035182:TATA Box Binding Protein-Like Proteins / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; C099555:CD 437; C499319:COL11A2 protein, human; D002352:Carrier Proteins; D024161:Collagen Type XI; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012176:Retinoids; D035182:TATA Box Binding Protein-Like Proteins; C480637:TBPL2 protein, human; C486715:TXNIP protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human