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TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells.
Petruzzelli, Raffaella; Mariniello, Marta; De Cegli, Rossella; Catalano, Federico; Guida, Floriana; Di Schiavi, Elia; Polishchuk, Roman S.
Afiliación
  • Petruzzelli R; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
  • Mariniello M; Institute of Physiology, Zürich University, Winterthurerstr. 190, CH-8057 Zürich, Switzerland.
  • De Cegli R; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
  • Catalano F; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
  • Guida F; Institute of Biosciences and BioResources (IBBR), CNR, 80131 Naples, Italy.
  • Di Schiavi E; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, 16132 Genoa, Italy.
  • Polishchuk RS; Institute of Biosciences and BioResources (IBBR), CNR, 80131 Naples, Italy.
Cells ; 11(2)2022 01 10.
Article en En | MEDLINE | ID: mdl-35053335
ABSTRACT
ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Platino (Metal) / Regulación Neoplásica de la Expresión Génica / Resistencia a Antineoplásicos / Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice / ATPasas Transportadoras de Cobre Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Cells Año: 2022 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Platino (Metal) / Regulación Neoplásica de la Expresión Génica / Resistencia a Antineoplásicos / Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice / ATPasas Transportadoras de Cobre Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Cells Año: 2022 Tipo del documento: Article País de afiliación: Italia