Apigenin Sensitizes Prostate Cancer Cells to Apo2L/TRAIL by Targeting Adenine Nucleotide Translocase-2

Abstract

Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human Apo2L/TRAIL has been under clinical trials, whereas various kinds of malignant tumors have resistance to Apo2L/TRAIL. We and others have shown that several anticancer agents and flavonoids overcome resistance to Apo2L/TRAIL by upregulating death receptor 5 (DR5) in malignant tumor cells. However, the mechanisms by which these compounds induce DR5 expression remain unknown. Here we show that the dietary flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), resulting in enhancement of Apo2L/TRAIL-induced apoptosis by upregulation of DR5. Apigenin and genistein, which are major flavonoids, enhanced Apo2L/TRAIL-induced apoptosis in cancer cells. Apigenin induced DR5 expression, but genistein did not. Using our method identifying the direct targets of flavonoids, we compared the binding proteins of apigenin with those of genistein. We discovered that ANT2 was a target of apigenin, but not genistein. Similarly to apigenin, knockdown of ANT2 enhanced Apo2L/TRAIL-induced apoptosis by upregulating DR5 expression at the post-transcriptional level. Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest that apigenin upregulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by binding and inhibiting ANT2. We propose that ANT2 inhibitors may contribute to Apo2L/TRAIL therapy.

The pleiotropic regulation of cyclin D1 by newly identified sesaminol-binding protein ANT2

“…We then generated sesaminol-immobilized FG beads, as we previously reported 40, 41 (Figure 2a). We next incubated sesaminol-immobilized beads with whole-cell extracts of MCF7 cells to purify sesaminol-binding proteins.…”

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

“…While ANT-2 has an anti-apoptotic function, it acts as a direct inhibitor of the MPT function by favoring the import of ATP into mitochondria and maintaining m-state of ANT (Chevrollier et al 2011). Moreover, ANT-2 knockdown has been shown to enhance apoptosis due to the elevated ROS levels (Oishi et al 2013). The increased ANT-1 expression and decreased ANT-2 expression (Fig.…”

Polyphenols as mitochondria-targeted anticancer drugs

“…Quercetin (a flavonol widely distributed in plants) inhibited ANT by 46% at the concentration of 50 μM in mitochondria isolated from rat kidney cortex [52]. Tested at 20 μM, apigenin (a flavone found in many fruits, vegetables, and herbs, particularly parsley, celery, and chamomile) was also shown to bind and inhibit ANT, which resulted in post-transcriptional upregulation of death receptor 5 (DR5) and enhancement of APO-2L/TRAIL-induced apoptosis in human prostate cancer DU145 cells [53]. In contrast, genistein (an isoflavone found in soybeans, among others) was inactive as ANT inhibitor.…”