Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

Hernández-Reséndiz, Ileana ; Pacheu-Grau, David (Universidad de Zaragoza) ; Sánchez, Araceli ; Pardo, Luis A.

Resumen: Reprogramming of energy metabolism constitutes one of the hallmarks of cancer and is, therefore, an emerging therapeutic target. We describe here that the potassium channel Kv10.1, which is frequently overexpressed in primary and metastatic cancer, and has been proposed a therapeutic target, participates in metabolic adaptation of cancer cells through regulation of mitochondrial dynamics. We used biochemical and cell biological techniques, live cell imaging and high-resolution microscopy, among other approaches, to study the impact of Kv10.1 on the regulation of mitochondrial stability. Inhibition of Kv10.1 expression or function led to mitochondrial fragmentation, increase in reactive oxygen species and increased autophagy. Cells with endogenous overexpression of Kv10.1 were also more sensitive to mitochondrial metabolism inhibitors than cells with low expression, indicating that they are more dependent on mitochondrial function. Consistently, a combined therapy using functional monoclonal antibodies for Kv10.1 and mitochondrial metabolism inhibitors resulted in enhanced efficacy of the inhibitors. Our data reveal a new mechanism regulated by Kv10.1 in cancer and a novel strategy to overcome drug resistance in cancers with a high expression of Kv10.1.

Idioma: Inglés

DOI: 10.3390/cancers12040920

Año: 2020

Publicado en: Cancers 12, 4 (2020), 920 [20 pp.]
ISSN: 2072-6694

Factor impacto JCR: 6.639 (2020)

Categ. JCR: ONCOLOGY rank: 51 / 241 = 0.212 (2020) - Q1 - T1

Factor impacto SCIMAGO: 1.818 - Oncology (Q1) - Cancer Research (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)