The Role of Heat Shock Protein-90 in the Pathogenesis of Birt-Hogg-Dubé and Tuberous Sclerosis Complex Syndromes

Woodford, Mark R.; Backe, Sarah J.; Sager, Rebecca; Bourboulia, Dimitra; Bratslavsky, Gennady; Mollapour, Mehdi

doi:10.1016/j.urolonc.2020.03.016

“…Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressors. In addition to neural associations that include epilepsy, subependymal giant cell astrocytomas (SEGA), intellectual disability, and autism, TSC is also characterized by cutaneous, pulmonary, and renal manifestations, similar to BHD [ 23 , 55 , 56 ]. These include facial fibrofolliculomas, pulmonary lymphangiomyomatosis, and renal angiomyolipomas (AML).…”

Section: Tsc1mentioning

confidence: 99%

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

Backe

¹

,

Sager

²

,

Meluni

³

et al. 2022

Self Cite

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Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.

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“…HSP90 regulates the proper conformation, function and activity of multiple proteins (about 200 ‘client’ proteins) by protecting them from proteasome-mediated degradation. HSP90 expression is upregulated in many forms of cancer, and is thought to promote/enable malignant transformation, tumor progression, invasion, metastasis, and/or angiogenesis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

Mrozek

¹

,

Bajaj

²

,

Guo

³

et al. 2021

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Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

show abstract

“…HSP90 regulates the proper conformation, function and activity of multiple proteins (about 200 ‘client’ proteins) by protecting them from proteasome-mediated degradation. HSP90 expression is upregulated in many forms of cancer, and is thought to promote/enable malignant transformation, tumor progression, invasion, metastasis, and/or angiogenesis (17, 18).…”

Section: Introductionmentioning

confidence: 99%

Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

Em

¹

,

Bajaj

²

,

Guo

³

et al. 2021

Preprint

0

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Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

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The Role of Heat Shock Protein-90 in the Pathogenesis of Birt-Hogg-Dubé and Tuberous Sclerosis Complex Syndromes

Cited by 6 publications

References 53 publications

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

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