MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant ovarian cancer cells via AKT degradation.
Int J Oncol
; 54(5): 1833-1842, 2019 May.
Article
en En
| MEDLINE
| ID: mdl-30816444
ABSTRACT
Chemoresistance is one of most critical clinical problems encountered when treating patients with ovarian cancer, due to the fact that the disease is usually diagnosed at advanced stages. Metformin is used as a firstline drug for the treatment of type 2 diabetes; however, drug repositioning studies have revealed its antitumor effects, mainly mediated through AMPactivated protein kinase (AMPK) activation and AKT/mammalian target of rapamycin (mTOR) pathway inhibition in various types of cancer, including drugresistant cancer cells. The current study revealed that the novel antitumor mechanism of metformin is mediated by regulation of mitochondrial E3 ubiquitin protein ligase 1 (MUL1) expression that negatively regulates AKT. The results demonstrated that metformin decreased the expression of AKT protein levels via MUL1 E3 ligase. In addition, metformin increased both mRNA and protein levels of MUL1 and promoted degradation of AKT in a proteasomedependent manner. Silencing MUL1 expression suppressed the metforminmediated AKT degradation and its downstream effects. Cell cycle analysis and a clonogenic assay demonstrated that knockdown of MUL1 significantly diminished the antitumor effects of metformin. Together, these data indicate that MUL1 regulates metforminmediated AKT degradation and the antitumor effects of metformin in chemoresistant ovarian cancer cell lines.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
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Resistencia a Antineoplásicos
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Ubiquitina-Proteína Ligasas
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Proteínas Proto-Oncogénicas c-akt
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Metformina
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Int J Oncol
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article