Geldanamycin inhibits TGF-beta signaling through induction of Hsp70.
Dysregulation of transforming growth factor-beta (TGF-beta) signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-beta signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-beta signaling by the Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-beta signaling, as evidenced by inhibition of TGF-beta-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-beta type I and type II receptors through a proteasome-dependent pathway. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-beta signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-beta signaling by GA. Furthermore, Hsp70 interacted directly with TGF-beta receptors following GA treatment. Our results suggest that GA-mediated induction of Hsp70 and its subsequent interaction with TGF-beta receptors plays a crucial role in inhibition of TGF-beta signaling.
Yun
Chang-Hyun
CH
Lee Gi Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo, Yeonsu, Incheon 406-840, Republic of Korea.
Yoon
Sun-Young
SY
Nguyen
Thuy Trang
TT
Cho
Han-Yang
HY
Kim
Tae-Hyun
TH
Kim
Shin-Tae
ST
Kim
Byung-Chul
BC
Hong
Young-Soo
YS
Kim
Seong-Jin
SJ
Lee
Ho-Jae
HJ
D016227:Benzoquinones / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C001277:geldanamycin