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Targeting Hsp90 in urothelial carcinoma.

Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, Bourboulia D - Oncotarget (2015)

Bottom Line: Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs.The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation.Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

ABSTRACT
Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

No MeSH data available.


Related in: MedlinePlus

Hsp90 chaperone cycleATP binding to the N-terminal domain of Hsp90 (red) in an “open” conformation promotes transient dimerization of the N-domains “closed” conformation leading to ATP hydrolysis [38]. The co-chaperones such as Aha1, Cdc37, HOP and p23 and post-translational modification influence the rate of ATP hydrolysis. Domain labeling is as follows: N, N-domain (red); CL, charged linker (black); M, M-domain (purple); C, C-domain (blue).
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Figure 2: Hsp90 chaperone cycleATP binding to the N-terminal domain of Hsp90 (red) in an “open” conformation promotes transient dimerization of the N-domains “closed” conformation leading to ATP hydrolysis [38]. The co-chaperones such as Aha1, Cdc37, HOP and p23 and post-translational modification influence the rate of ATP hydrolysis. Domain labeling is as follows: N, N-domain (red); CL, charged linker (black); M, M-domain (purple); C, C-domain (blue).

Mentions: Hsp90 plays an important role in urothelial carcinoma biology, as well as in carcinogenesis of other tumors, by its function as a molecular chaperone that cancer cells utilize to protect over-expressed or mutated oncoproteins from misfolding and degradation [21–25]. Proteins chaperoned by Hsp90, also known as clients, control numerous cellular processes that support tumor growth and metastasis, including signal transduction, angiogenesis, anti-apoptotic pathways and tumor invasion [26]. Hsp90 is a homo-dimeric protein that comprises of three domains: i) the N-terminal domain, containing nucleotide, drug and co-chaperone (proteins that regulate Hsp90 function) binding sites; ii) the middle (M) domain, which provides binding motif for client proteins and other co-chaperones, and iii) the C-terminal domain containing a dimerization motif and binding sites for yet other co-chaperones. An unstructured charged-linker region connects N and M domains and, therefore, provides conformational flexibility to the Hsp90 protein [27–37] (Figure 2). Hsp90 function is coupled to its ATPase activity [38] and this, in turn, provides conformational cycle that is “fine-tuned” by co-chaperones and post-translational modifications such phosphorylation, acetylation, ubiquitination, oxidation, methylation, S-nitrosylation and SUMOylation [39–44] (Figure 2). Clinically evaluated Hsp90 inhibitors disrupt the chaperone cycle by occupying the nucleotide-binding pocket in the N-domain, therefore, inhibiting the ATPase activity [32, 45]. As a result, Hsp90-dependent client proteins are ubiquitinated and degraded in the proteasome [43, 46–48].


Targeting Hsp90 in urothelial carcinoma.

Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, Bourboulia D - Oncotarget (2015)

Hsp90 chaperone cycleATP binding to the N-terminal domain of Hsp90 (red) in an “open” conformation promotes transient dimerization of the N-domains “closed” conformation leading to ATP hydrolysis [38]. The co-chaperones such as Aha1, Cdc37, HOP and p23 and post-translational modification influence the rate of ATP hydrolysis. Domain labeling is as follows: N, N-domain (red); CL, charged linker (black); M, M-domain (purple); C, C-domain (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496161&req=5

Figure 2: Hsp90 chaperone cycleATP binding to the N-terminal domain of Hsp90 (red) in an “open” conformation promotes transient dimerization of the N-domains “closed” conformation leading to ATP hydrolysis [38]. The co-chaperones such as Aha1, Cdc37, HOP and p23 and post-translational modification influence the rate of ATP hydrolysis. Domain labeling is as follows: N, N-domain (red); CL, charged linker (black); M, M-domain (purple); C, C-domain (blue).
Mentions: Hsp90 plays an important role in urothelial carcinoma biology, as well as in carcinogenesis of other tumors, by its function as a molecular chaperone that cancer cells utilize to protect over-expressed or mutated oncoproteins from misfolding and degradation [21–25]. Proteins chaperoned by Hsp90, also known as clients, control numerous cellular processes that support tumor growth and metastasis, including signal transduction, angiogenesis, anti-apoptotic pathways and tumor invasion [26]. Hsp90 is a homo-dimeric protein that comprises of three domains: i) the N-terminal domain, containing nucleotide, drug and co-chaperone (proteins that regulate Hsp90 function) binding sites; ii) the middle (M) domain, which provides binding motif for client proteins and other co-chaperones, and iii) the C-terminal domain containing a dimerization motif and binding sites for yet other co-chaperones. An unstructured charged-linker region connects N and M domains and, therefore, provides conformational flexibility to the Hsp90 protein [27–37] (Figure 2). Hsp90 function is coupled to its ATPase activity [38] and this, in turn, provides conformational cycle that is “fine-tuned” by co-chaperones and post-translational modifications such phosphorylation, acetylation, ubiquitination, oxidation, methylation, S-nitrosylation and SUMOylation [39–44] (Figure 2). Clinically evaluated Hsp90 inhibitors disrupt the chaperone cycle by occupying the nucleotide-binding pocket in the N-domain, therefore, inhibiting the ATPase activity [32, 45]. As a result, Hsp90-dependent client proteins are ubiquitinated and degraded in the proteasome [43, 46–48].

Bottom Line: Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs.The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation.Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

ABSTRACT
Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

No MeSH data available.


Related in: MedlinePlus