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

Chai, Ryan C.; Kouspou, Michelle M.; Lang, Benjamin; Nguyễn, Chí Công; Kraan, A. Gabrielle J. van der; Vieusseux, Jessica L.; Lim, Ren Yik; Gillespie, Matthew T.; Benjamin, Ivor J.; Quinn, Julian M.W.; Price, John T.

doi:10.1074/jbc.m113.530626

Cited by 24 publications

(28 citation statements)

References 65 publications

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“…Previous studies show that 17‐AAG‐dependent HSP90 inhibition leads to the transient activation of Src kinase and promotes osteoclastogenesis, resulting in promoted bone metastasis . This effect was also seen in other small molecule compounds that bind the N‐terminal ATPase domain of HSP90 and subsequently induce a heat shock response via heat shock transcription factor 1 (HSF1) . Unlike transforming growth factor‐beta (TGF‐β), HSP90 inhibitors stimulate the late phase of osteoclast differentiation in the presence of receptor activator of nuclear factor kappa‐B ligand (RANKL) .…”

Section: Discussionmentioning

confidence: 97%

Organ‐specific efficacy of HSP90 inhibitor in multiple‐organ metastasis model of chemorefractory small cell lung cancer

Takeuchi

Fukuda

Arai

et al. 2015

Intl Journal of Cancer

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Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous "client proteins." Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines-regardless of their chemosensitivityvia the decreased expression of client proteins, including the proto-oncogene c-Raf (also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related deaths worldwide.1 It is histologically classified in two types: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). While targeted molecular therapies have led to improved treatment outcomes for NSCLC, no progress has been made on therapeutic strategies for SCLC over the past two decades.2 SCLC accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs such as the brain, liver, and bones.3 Accordingly, about 70% of patients with SCLC present with extensive disease (ED) and distant metastases. Cisplatin-based chemotherapy is standard for patients with ED-SCLC, 4 but despite an initial response, most patients develop chemoresistant disease within 6 months and often become refractory to salvage chemotherapy. 4,5Thus, the median range for ED-SCLC survival is 8-13 months. 6 To improve the poor prognosis of SCLC, it is essential to develop novel effective therapies capable of limiting the progression of multiple-organ metastasis in chemorefractory SCLC. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of numerous "client proteins." 7 Because many of its client proteins-including EGFR (epithelial growth factor receptor), HER2 (human epithelial growth factor receptor 2), AKT and c-Raf (also known as RAF1)-are important participants in the pathways that drive tumor cell survival, proliferation and progression, HSP9...

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Section: Discussionmentioning

confidence: 97%

Organ‐specific efficacy of HSP90 inhibitor in multiple‐organ metastasis model of chemorefractory small cell lung cancer

Takeuchi

Fukuda

Arai

et al. 2015

Intl Journal of Cancer

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“…Moreover, the use of HSP90 inhibitors in tumors associated with bone lesions is actually controversial. Contradictory reports suggested that blocking HSP90 inhibits both primary tumor growth and bone metastases (13,24), while other recent studies have reported that HSP90 inhibition using 17-AAG promotes prostate and breast cancer growth in bone by inducing both osteoclast differentiation and activation via induction of Src signaling or HSF1-dependent mechanism (14,15,46). These results highlight a potential risk to use HSP90 inhibitors therapies in patients with tumor-associated bone lesions.…”

Section: Discussionmentioning

confidence: 67%

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Ory

Baud’huin

Verrecchia

et al. 2016

Clinical Cancer Research

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Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma.Experimental Design: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14 þ monocytes.

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“…NFATc1 activation is required for the induction of essential osteoclast transcription factors, such as microphthalmia-associated transcription factor (MITF) (44). In addition to the NFATc1-MITF pathway, MITF is upregulated by HSP70 (44). Although 17-AAG is a known potent cytotoxic drug, it is associated with side effects that cause bone loss due to increases in HSP70-MITF.…”

Section: The Effects Of Calcineurin Inhibition On Apoptosis and Prolimentioning

confidence: 99%

“…PPP3CA protein levels, but not mRNA expression, decreased in differentiated osteoclasts treated with panobinostat ( Figure 6B). NFATc1 activation is required for the induction of essential osteoclast transcription factors, such as microphthalmia-associated transcription factor (MITF) (44). In addition to the NFATc1-MITF pathway, MITF is upregulated by HSP70 (44).…”

Section: The Effects Of Calcineurin Inhibition On Apoptosis and Prolimentioning

confidence: 99%

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

et al. 2016

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

Cited by 24 publications

References 65 publications

Organ‐specific efficacy of HSP90 inhibitor in multiple‐organ metastasis model of chemorefractory small cell lung cancer

Organ‐specific efficacy of HSP90 inhibitor in multiple‐organ metastasis model of chemorefractory small cell lung cancer

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

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