Heat shock protein 90 inhibitor radicicol attenuates matrix metalloproteinase expression in human monocytic cells (P4153)

Abstract The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting target for anti-tumor and immunoregulatory therapy. In this study, we investigated the inhibitory effects and mechanism of radicicol, as a HSP90 inhibitor, on human monocytic matrix metalloproteinases (MMPs) and pro-inflammatory cytokine expression. Radicicol exhibited concentration-dependent inhibition of MMP-9 enzymatic activation induced by either tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) in human monocytic THP-1 cells. Western blot and RT-PCR analyses showed that radicicol concentration-dependently suppressed LPS-induced monocytic MMP-9 protein and mRNA expression. It was also shown that radicicol enhanced HSP70 expression. Besides, we clearly found that radicicol restore the degradation of inhibitor-kappaB-alpha and abrogate NF-kappaB reporter gene expression in activated THP-1 cells. In addition, activation of Akt and its total protein expression were reduced by radicicol. Furthermore, radicicol presented an inhibitory effect on both TNF-alpha and interleukin-6 productions by ELISA. In conclusion, we demonstrate that radicicol might involve interference with the NF-kappaB or Akt signaling pathway to attenuate production of MMP-9 and pro-inflammatory cytokines. These results provide a new opportunity for the development of anti-leukemia and cachexia-relief strategies.