Abstract 2279: Adenine nucleotide translocase-2 is a key molecule in the enhancement of TRAIL sensitivity by flavonoids

Abstract

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine which belongs to the tumor necrosis factor family. TRAIL binds to death receptor (DR) 4 and DR5 and selectively induces apoptosis in various malignant tumors, but not in normal cells. Therefore, TRAIL is an attractive cancer therapeutic agent. However, several malignant tumors have resistance to TRAIL and overcoming this resistance is essential for chemotherapy using the TRAIL pathway. Anticancer agents such as bortezomib, etoposide, doxorubicin, and irinotecan have been reported to upregulate DR5 and sensitize cancer cells to TRAIL in vitro and in vivo. Since these agents cause various adverse effects, we and others have screened dietary compounds inducing DR5 expression and identified several flavonoids as DR5 inducers. For instance, dietary flavonoid apigenin and quercetin enhance TRAIL sensitivity by upregulating DR5. However, the mechanisms by which these flavonoids upregulate DR5 are unknown. To elucidate the mechanisms by which these flavonoids induce DR5, we explored the proteins binding to apigenin and quercetin, but not the flavonoid genistein which did not induce DR5. We used magnetic FG beads, which recently revealed the target of thalidomide and the mechanism of thalidomide teratogenicity. We identified ANT2 as a binding protein of flavonoids, apigenin and quercetin, upregulating DR5. As with the treatment of apigenin and quercetin, knockdown of ANT2 enhanced TRAIL-induced apoptosis by upregulating DR5. Moreover, knockdown of ANT2 attenuated the enhancement of TRAIL-mediated apoptosis by apigenin and quercetin. In the present study, we show that ANT2 is a target of flavonoids which upregulate DR5 and sensitize malignant tumor cells to TRAIL. Citation Format: Masakatsu Oishi, Yosuke Iizumi, Takashi Ueda, Saya Ito, Terukazu Nakamura, Fumiya Hongo, Yoshio Naya, Tsuneharu Miki, Toshiyuki Sakai. Adenine nucleotide translocase-2 is a key molecule in the enhancement of TRAIL sensitivity by flavonoids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2279. doi:10.1158/1538-7445.AM2014-2279