Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Abstract

Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

Molecular Stress-inducing Compounds Increase Osteoclast Formation in a Heat Shock Factor 1 Protein-dependent Manner

“…1A), and, consistent with previous findings (20,21), 17-AAG also increased RANKLstimulated osteoclast formation in a dose-dependent manner (Fig. 1, B and C).…”

“…In addition to 17-AAG, we have demonstrated that other structurally unrelated HSP90 inhibitors also enhance osteoclast formation (20,22). To date, the mechanism by which HSP90 inhibitors stimulate osteoclast formation has not been clearly defined, although Src kinase and the elevated expression of the essential osteoclast transcription factor microphthalmia-associated transcription factor (MITF) may play roles (21,22). However, HSP90 inhibition itself seems unlikely to be directly critical in 17-AAG actions on osteoclasts because many of the RANKL signaling pathways required for osteoclast formation (e.g.…”

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

“…Additionally, 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG); retaspimycin hydrochloride (IPI-504), two Hsp90 inhibitors, provided no benefit to CRPC patients (55,56). The poor therapeutic effect of Hsp90 inhibitors may be the consequence of inhibiting widespread client proteins and may thereby result in activation of oncogenic signaling pathways such as Src and co-chaperone Hsp27 up-regulation (57,58). Inhibition of Cdc37, a co-chaperone of Hsp90 that is overexpressed in cancer cells, may represent a better drug target in cancers (59).…”

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

“…Cytoplasmic c-Src is a well-studied HSP90 client protein and its interaction with HSP90 is required for Src maturation (47). However, we have shown previously that pharmacological disruption of HSP90 association with mature c-Src induces a transient but distinct increase in c-Src activity (48,49). Release of enzymatically competent c-Src from HSP90 relieves its auto-inhibition and permits phosphorylation of Tyr-416 in the activation loop.…”