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1.
Biochem Biophys Res Commun ; 677: 141-148, 2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37586212

RESUMO

The increased stability of mutant p53 (Mutp53) plays a crucial role in its gain of function, making proteins involved in its stabilization promising targets for drug intervention. Although curcumin is known to exhibit anti-cancer effects, its role as a deubiquitinase (DUB) inhibitor in Mutp53 destabilization remains poorly explored. Our study demonstrates that curcumin treatment induced ubiquitination and destabilization of Mutp53 but not Wild-type p53 (WTp53) in cancer cells. Furthermore, proteasome and lysosome inhibitors failed to reverse the effect of curcumin, indicating Mutp53 destabilization is possibly via an alternate mechanism. Intriguingly, curcumin treatment also resulted in the nuclear aggregation of the Mutp53 protein, which was rescued by combined Dithiothreitol (DTT) treatment. Similar to curcumin, a broad-spectrum deubiquitinase inhibitor induced Mutp53 aggregation implying curcumin possibly acts by inhibiting deubiquitinases. Additionally, curcumin treatment inhibited colony-forming abilities, induced cytoplasmic vacuolation, and cell death selectively in Mutp53-expressing cells. Collectively, our study highlights the potential of curcumin as a promising therapeutic agent for targeting Mutp53-expressing cancer cells.


Assuntos
Curcumina , Neoplasias , Curcumina/farmacologia , Linhagem Celular Tumoral , Proteína Supressora de Tumor p53/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Enzimas Desubiquitinantes/metabolismo , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética
2.
Br J Cancer ; 125(4): 547-560, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34079080

RESUMO

BACKGROUND: Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. METHODS: Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. RESULTS: Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. CONCLUSION: We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Estabilidade Proteica , Análise de Sobrevida , Ubiquitina Tiolesterase/genética , Ubiquitinação
3.
FEBS J ; 285(7): 1251-1276, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29427328

RESUMO

Keratin 8/18, the predominant keratin pair of simple epithelia, is often aberrantly expressed in various squamous cell carcinomas (SCCs) including skin SCC. Its aberrant expression is correlated with increased invasiveness and poor prognosis of the same, although the underlying mechanism is still unclear. A previous report from our laboratory has shown K8-mediated regulation of α6ß4 integrin signaling and thereby tumorigenic potential of oral SCC-derived cells. Another study on transgenic mouse model has shown that during skin carcinogenesis, K8 favors conversion of papillomas toward malignancy. In order to understand the role of K8 and allied mechanism in skin SCC, K8 was stably knocked down in a skin epidermoid carcinoma-derived A431 cells. K8 downregulation significantly reduced the tumorigenic potential of these cells. In agreement with our phenotypic data, differential quantitative proteomics followed by IPA analysis showed altered expression of many proteins associated with biological functions including 'Cancer', 'Cellular movement', 'Cell death and survival', and 'Cellular morphology'. Some of these proteins were TMS1, MARCKSL1, RanBP1, 14-3-3γ, Rho-GDI2, etc. Furthermore, to our surprise, there was a significant reduction in K17 protein stability upon loss of K8, probably due to its caspase-mediated degradation. This was supported by altered TMS1-NF-κB signaling, leading to increased apoptotic sensitivity of A431 cells which in turn affected 'Cell death and survival'. Moreover, MARCKSL1-Paxillin1-Rac axis was found to be deregulated bestowing a possible mechanism behind altered 'Cellular movement' pathway. Altogether our study unravels a much broader regulatory role of K8, governing multiple signaling pathways and consequently regulating oncogenic potential of skin SCC-derived cells. DATABASE: Proteome Xchange Consortium via PRIDE database (dataset identifier PXD007206).


Assuntos
Queratina-18 , Queratina-8 , Transdução de Sinais/genética , Carcinogênese/genética , Sobrevivência Celular/genética , Regulação da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Queratina-18/genética , Queratina-18/metabolismo , Queratina-8/genética , Queratina-8/metabolismo , Proteômica
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