Mitochondrial‐targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells

Abstract

Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.

The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells

“…According to the report by Vivas-Mejía et al, the expression of PRX3 was down-regulated and the apoptosis was enhanced in the acute promyelocytic leukemia (APL)-derived cells treated with arsenic trioxide (ATO) (VivasMejía et al 2009). The similar mechanism was found, respectively, in breast cancer cells treated with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (Liu et al 2010) and in mesothelioma cells treated with nitroxides (Cunniff et al 2013). Thiostrepton (TS) is a thiazole antibiotic that has been shown to has modest antitumor activity in a mouse model (Halasi et al 2010).…”

“…Afterward, Chiribau et al reported that FOXO3A, a forkhead box transcription factor, mediated PRX3 expression resulting in the resistance to oxidative stress in human cardiac fibroblasts (Chiribau et al 2008), and Jeong et al confirmed that the expression of PRX3 was partially dependent on FOXO3A in pheochromocytoma cells . Another study conducted by Cunniff et al reported the coexistence of cytoplasmic FOXM1 and mitochondrial PRX3 in mesothelioma cells (Cunniff et al 2013). One more candidate regulator for PRX3 might be p53.…”

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism

“…Previous research has shown that AMPK represses the FOXM1 transcription factor expression via inhibition of the AKT/FOXO3 signaling cascade, leading to regression of cervical cancer cell growth [39]. Treatment of lung cancer cells with Mito-CP resulted in the inhibition of FOXM1 [40]. This, combined with the possibility that Mito-CP and Mito-CP-Ac could activate AMPK and decrease FOXM1 expression, underscores the importance of the AKT/FOXO3/FOXM1 signaling pathway as a potential therapeutic target for mitochondria-targeted cationic drugs.…”

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…cell cycle progression, especially at the G2/M phase [121]. The same group also showed that some compounds targeted to mitochondria were able to reduce MM cell viability by increasing mitochondrial oxidant production and inhibiting the expression of FOXM1 (forkhead box M1), a redox-responsive transcription factor that regulates the expression of PRX3 [122].…”