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.