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1.
Chemistry ; 26(43): 9459-9465, 2020 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-32167602

RESUMEN

Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein-protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation.


Asunto(s)
Carcinógenos/química , Proteínas de Ciclo Celular/química , Chaperoninas/química , Proteínas HSP90 de Choque Térmico/química , Chaperonas Moleculares/química , Carcinógenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Pliegue de Proteína
2.
Nat Struct Mol Biol ; 28(8): 662-670, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34381247

RESUMEN

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.


Asunto(s)
Glucólisis/fisiología , Lactato Deshidrogenasa 5/antagonistas & inhibidores , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Dominio Catalítico/fisiología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Humanos , Lactato Deshidrogenasa 5/metabolismo , Transducción de Señal
3.
Expert Opin Ther Targets ; 24(9): 923-936, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32744123

RESUMEN

INTRODUCTION: Renal cell carcinoma (RCC) is a heterogeneous group of cancers that can occur sporadically or as a manifestation of various inherited syndromes. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is one such inherited syndrome that predisposes patients to HLRCC-associated RCC. These tumors are notoriously aggressive and often exhibit early metastases. HLRCC results from germline mutations in the FH gene, which encodes the citric acid cycle enzyme fumarate hydratase (FH). FH loss leads to alterations in oxidative carbon metabolism, necessitating a switch to aerobic glycolysis, as well as a pseudohypoxic response and consequent upregulation of various pro-survival pathways. Mutations in FH also alter tumor cell migratory potential, response to oxidative stress, and response to DNA damage. AREAS COVERED: We review the mechanisms by which FH loss leads to HLRCC-associated RCC and how these mechanisms are being rationally targeted. EXPERT OPINION: FH loss results in the activation of numerous salvage pathways for tumor cell survival in HLRCC-associated RCC. Tumor heterogeneity requires individualized characterization via next-generation sequencing, ultimately resulting in HLRCC-specific treatment regimens. As HLRCC-associated RCC represents a classic Warburg tumor, targeting aerobic glycolysis is particularly promising as a future therapeutic avenue.


Asunto(s)
Carcinoma de Células Renales/terapia , Fumarato Hidratasa/genética , Neoplasias Renales/terapia , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Leiomiomatosis/complicaciones , Leiomiomatosis/genética , Terapia Molecular Dirigida , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/genética , Estrés Oxidativo/genética , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/genética , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/genética
4.
Urol Case Rep ; 13: 19-21, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28435787

RESUMEN

High grade mucinous urothelial carcinoma is a rare pathological variant. There is still controversy as to its nomenclature and classification. We report the case of a 64 year old female with history of pelvic pain who was incidentally discovered to have a left upper pole renal mass. Left nephroureterectomy was performed and histopathological examination revealed high grade mucinous urothelial carcinoma. Accurate diagnosis of this distinct pathological entity will allow for better understanding of phenotypic behavior and inform best treatment strategies.

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