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.
Highlights
Prostate cancer is the second commonly diagnosed cancer and the sixth leading cause of male cancer-related death in the world [1]
Apigenin induced death receptor 5 (DR5) protein expression but genistein did not (Fig. 1B), while apigenin did not upregulate DR5 mRNA (Fig. 1C and S3). These results suggest that apigenin enhances Apo2 ligand (Apo2L)/ tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-induced apoptosis by post-transcriptionally upregulating DR5
Ribosomal protein S9 (RPS9) was identified as a binding protein of these flavonoids (Fig. 2B). These results indicate that adenine nucleotide translocase-2 (ANT2) is a binding protein of apigenin which induces DR5 expression
Summary
Prostate cancer is the second commonly diagnosed cancer and the sixth leading cause of male cancer-related death in the world [1]. Androgen withdrawal therapy is effective in treating advanced prostate cancer, most patients exhibit resistance to this therapy [2]. It was reported that docetaxel plus prednisone was effective for hormone-refractory prostate cancer [3]. New strategies are needed to treat hormone-refractory prostate cancer. Apo2L/TRAIL binds to death receptor 4 (DR4) and death receptor 5 (DR5) and selectively induces apoptosis in various malignant tumors, but not in normal cells [5,6]. We and others have screened dietary compounds sensitizing cancer cells to Apo2L/TRAIL and identified several polyphenols as DR5 inducers [9,10,11,12,13,14]. The mechanisms by which these polyphenols upregulate DR5 are unknown
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