Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53

Abstract

Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel anticancer therapeutics, we unexpectedly identified auranofin as a potent anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated anticancer activity in ovarian cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose- and time-dependent manner. Auranofin treatment activates the pro-apoptotic caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and apoptosis in cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced apoptosis in ovarian cancer cells.

Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

“…Since it is known that FOXO3 can regulate cell survival and proliferation (cycle control) [11] and that activation of FOXO3 can promote cellular apoptosis [12, 17–19], we sought to determine whether FOXO3 is necessary for regulating TFP- or BPD-mediated inhibition of cell survival and proliferation in TNBC cells. We silenced endogenous FOXO3 in BT549 and MDA-MB-231 cells by transfecting these cells with FOXO3-siRNA or Control-siRNA (Figure 6A, 6C).…”

“…FOXO3 is a key protein that controls the transcription of a number of genes crucial for regulating cell cycle control [11], DNA damage and stress responses [12–15], aging and longevity [12, 16], cellular apoptosis [12, 17–19], and suppression of cancer [20–23] in animal and human cells; gene knockout findings reveal FOXO3′s additional functions in tumor suppression [24] and the maintenance of the hematopoietic stem cell pool [25]. While multiple mechanisms have been shown to regulate FOXO3 activity, phosphorylation inhibits FOXO3 nuclear translocation that controls its regulation and function.…”

“…Consequently, loss of function of FOXO3 has been linked to tumorigenesis and poor patient survival in breast cancer [20, 22, 23] and other cancers such as lung cancer [26], prostate cancer [27], and ovarian cancer [28]. In the absence of survival signal stimulation, the Akt pathway is inactivated and its cellular targets such as FOXO3 can translocate to the nucleus and induce the expression of cell cycle regulators (e.g., p27Kip1) that lead to cell cycle arrest, or upregulate certain genes (e.g., Fas-ligand and Bim) that result in apoptosis depending on the physiological conditions and the cell types [11, 12, 17–19]. The nuclear exclusion and translocation of FOXO3 into the cytoplasm inhibits FOXO3-dependent transcription.…”

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

“…Auranofin induces ER-stress response in cultured and primary chronic lymphocytic leukemia cells [35]. Auranofin also increases levels of pro-apoptotic proteins Bax and Bim and reduces anti-apoptotic protein Bcl-2 in ovarian carcinoma cells, and activates caspase-3-mediated apoptosis in a FOXO3-dependent manner [36]. Gold(III) and organogold(III) compounds have been reported as potential antitumor agents [37-39].…”

Enhanced Eryptosis Following Auranofin Exposure

“…The proapoptotic effect of auranofin has been attributed to increase of cytosolic Ca 2+ activity [17], thioredoxin (Trx)-2 reductase inhibition, GSH decline and oxidative stress [18][19][20][21][22][23][24][25], p38 protein kinase activation [26], FOXO3 activation [27], as well as annexin V expression and translocation [28]. Moreover, auranofin has been shown to inhibit PGE 2 formation [5].…”