MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant ovarian cancer cells via AKT degradation.

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.