Androgen receptor (AR) expression in estrogen receptor-positive (ER+) breast cancer (BC) correlates with lower tumor grade and a better clinical outcome. Additionally, in normal mammary epithelium or ER+ BC preclinical models, androgens counteract basal/ER-dependent proliferation. Here, we report an additional mechanism, underlining the protective role exerted by AR. Specifically, the activation of intracellular AR upregulates the Bcl-2-family protein BAD, and TCGA database analyses show that in ER+ BC, BAD expression is associated with better disease-free survival. Ligand-activated AR influences its own and BAD cellular compartmentalization by enhancing levels in the nucleus, as well as in mitochondrial fractions. In both compartments, BAD exerts unconventional functions. In the nucleus, BAD and AR physically interact and, upon androgen stimulation, are recruited at the AP-1 and ARE sites within the cyclin D1 promoter region, contributing to explaining the anti-proliferative effect of androgens in BC cells. Androgens cause an enrichment in BAD and AR content in the mitochondria, correlated with a decrease in mitochondrial function. Thus, we have defined a novel mechanism by which androgens modulate BAD expression, its mitochondria localization, and nuclear content to force its ability to act as a cell cycle inhibitor, strengthening the protective role of androgen signaling in estrogen-responsive BCs.

Glioblastoma (GB) is one of the most aggressive malignant brain tumors. Due to the high invasiveness of this cancer, surgical removal is often not possible, and relapses after surgery are very common, making current treatments ineffective. Developing new therapies or treatment combinations remains a major challenge in managing GB. Metformin (MET), an anti-diabetic medication, has recently gained attention for its potential anticancer effects. To better understand how MET inhibits GB growth at the molecular level, we studied its impact on survivin, a member of the inhibitor of apoptosis (IAP) family that is essential for GB cell survival, resistance to radio- and chemotherapy, and tumor recurrence. Using T98G and U87-MG cell lines, we performed cell viability, migration, and invasion assays, along with Western blot analysis, ChIP assays, and gene silencing experiments to examine key signaling pathways. We found that MET effectively inhibits the growth, viability, and invasiveness of GB cell lines through a molecular mechanism involving activation of the AMPK/FoxO3a/survivin pathway. In vivo studies support these findings, showing increased FoxO3a and decreased survivin in brain tissue sections from metformin-treated mice compared with untreated controls. These results suggest new possibilities for repurposing MET as an adjuvant treatment for GB.

For many types of cancer, pre-clinical studies have shown that dietary interventions and supplements can be effective in reducing the toxicity and increasing the efficacy of chemotherapeutics. In this context, the polyphenol curcumin is an attractive molecule. We have previously demonstrated that curcumin inhibits adrenocortical carcinoma (ACC) cell growth, has an impact on ACC cell metabolism, decreasing cholesterol availability and promoting glucose and glutamine metabolism. In this study, we evidenced that curcumin downregulates the transcription factors SF-1 and SREBPs and their targets, while inducing a ROS-dependent, HIF1α- and NRF2-mediated metabolic rewiring. NRF2 sustained an adaptive antioxidant mechanism dependent on glutamine, cysteine, and glycine uptake to support glutathione synthesis and avoid lipid peroxidation. Furthermore, the combination of curcumin with mitotane demonstrated synergistic effects in inhibiting ACC cell viability and reducing steroidogenic gene expression. These synergistic effects were observed with sub-therapeutic doses of mitotane, which are reached by patients who fail to attain the therapeutic plasma concentrations of the drug. Crucially, in vivo, curcumin administration to tumor-free mice significantly upregulated NRF2 expression and preserved liver tissue integrity. These results warrant further preclinical evaluation of the proposed combination therapy, particularly for those patients who fail to achieve or maintain mitotane plasma concentrations in the therapeutic range.