Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90.
Securin, the natural inhibitor of sister chromatid untimely separation, is a protooncogene overexpressed in tumors. Its protein levels correlate with malignancy and metastatic proneness. Dicoumarol, a long-established oral anticoagulant, is a new Hsp90 inhibitor that represses PTTG1/Securin gene expression and provokes apoptosis through a complex trait involving both intrinsic and extrinsic pathways. Dicoumarol activity as an Hsp90 inhibitor is confirmed by smaller levels of Hsp90 clients in treated cells and inhibition of in vivo heat shock luciferase activity recovery assays. Likewise, established Hsp90 inhibitors (17-allylamino-geldanamycin and novobiocin) repress PTTG1/Securin gene expression. Also, overexpression of human Hsp90 in yeast makes them hypersensitive to dicoumarol. Both apoptosis and PTTG1/Securin gene repression exerted by dicoumarol in cancer cells are independent of three of the most important signaling pathways affected by Hsp90 inhibition: nuclear factor-kappaB, p53, or Akt/protein kinase B signaling pathways. However, effects on PTTG1/Securin could be partially ascribed to inhibition of the Ras/Raf/extracellular signal-regulated kinase pathway. Overall, we show that expression of PTTG1/Securin gene is Hsp90 dependent and that dicoumarol is a bona fide Hsp90 inhibitor. These findings are important to understand the mode of action of Hsp90 inhibitors, mechanisms of action of dicoumarol, and Securin overexpression in tumors.
Hernández
Agustín
A
Instituto de Recursos Naturales y Agrobiología de Sevilla, Seville, Spain. ahernan@cica.es
López-Lluch
Guillermo
G
Bernal
Juan A
JA
Navas
Plácido
P
Pintor-Toro
José A
JA
D000925:Anticoagulants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D001728:Dicumarol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064249:Securin
D000925:Anticoagulants; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D001728:Dicumarol