USP32 confers cancer cell resistance to YM155 via promoting ER-associated degradation of solute carrier protein SLC35F2.

Chandrasekaran, Arun Pandian; Kaushal, Kamini; Park, Chang-Hwan; Kim, Kye-Seong; Ramakrishna, Suresh

Chandrasekaran, Arun Pandian; Kaushal, Kamini; Park, Chang-Hwan; Kim, Kye-Seong; Ramakrishna, Suresh.

Afiliación

Chandrasekaran AP; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
Kaushal K; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
Park CH; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
Kim KS; College of Medicine, Hanyang University, Seoul, South Korea.
Ramakrishna S; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.

Theranostics ; 11(20): 9752-9771, 2021.

Article en En | MEDLINE | ID: mdl-34815782

RESUMEN

Background: The most commonly preferred chemotherapeutic agents to treat cancers are small-molecule drugs. However, the differential sensitivity of various cancer cells to small molecules and untargeted delivery narrow the range of potential therapeutic applications. The mechanisms responsible for drug resistance in a variety of cancer cells are also largely unknown. Several deubiquitinating enzymes (DUBs) are the main determinants of drug resistance in cancer cells. Methods: We used CRISPR-Cas9 to perform genome-scale knockout of the entire set of genes encoding ubiquitin-specific proteases (USPs) and systematically screened for DUBs resistant to the clinically evaluated anticancer compound YM155. A series of in vitro and in vivo experiments were conducted to reveal the relationship between USP32 and SLC35F2 on YM155-mediated DNA damage in cancer cells. Results: CRISPR-based dual-screening method identified USP32 as a novel DUB that governs resistance for uptake of YM155 by destabilizing protein levels of SLC35F2, a solute-carrier protein essential for the uptake of YM155. The expression of USP32 and SLC35F2 was negatively correlated across a panel of tested cancer cell lines. YM155-resistant cancer cells in particular exhibited elevated expression of USP32 and low expression of SLC35F2. Conclusion: Collectively, our DUB-screening strategy revealed a resistance mechanism governed by USP32 associated with YM155 resistance in breast cancers, one that presents an attractive molecular target for anti-cancer therapies. Targeted genome knockout verified that USP32 is the main determinant of SLC35F2 protein stability in vitro and in vivo, suggesting a novel way to treat tumors resistant to small-molecule drugs.

Asunto(s)

Imidazoles/farmacología; Proteínas de Transporte de Membrana/metabolismo; Naftoquinonas/farmacología; Ubiquitina Tiolesterasa/metabolismo; Antineoplásicos/farmacología; Apoptosis/efectos de los fármacos; Línea Celular Tumoral; Supervivencia Celular/efectos de los fármacos; Daño del ADN; Enzimas Desubicuitinizantes/genética; Enzimas Desubicuitinizantes/metabolismo; Enzimas Desubicuitinizantes/farmacología; Resistencia a Antineoplásicos/genética; Resistencia a Antineoplásicos/fisiología; Expresión Génica/genética; Regulación Neoplásica de la Expresión Génica/genética; Humanos; Imidazoles/metabolismo; Proteínas Inhibidoras de la Apoptosis/metabolismo; Proteínas de Transporte de Membrana/genética; Naftoquinonas/metabolismo; Neoplasias/tratamiento farmacológico; Neoplasias/metabolismo; Proteínas Transportadoras de Solutos/metabolismo; Ubiquitina Tiolesterasa/genética; Proteasas Ubiquitina-Específicas/genética; Proteasas Ubiquitina-Específicas/metabolismo

Palabras clave

DNA damage; cell apoptosis; dose response; drug transport-cargo; human tumor tissues

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Transporte de Membrana / Naftoquinonas / Ubiquitina Tiolesterasa / Imidazoles Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Theranostics Año: 2021 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Australia

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