Abstract
Resveratrol has various attractive bioactivities, such as prevention of cancer, neurodegenerative disorders, and obesity-related diseases. Therefore, identifying its direct binding proteins is expected to discover druggable targets. Sirtuin 1 and phosphodiesterases have so far been found as the direct molecular targets of resveratrol. We herein identified 11 novel resveratrol-binding proteins, including the DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5, also known as p68), using resveratrol-immobilized beads. Treatment with resveratrol induced degradation of DDX5 in prostate cancer cells. Depletion of DDX5 caused apoptosis by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. Moreover, knockdown of DDX5 attenuated the inhibitory activities of resveratrol against mTORC1 signaling and cancer cell growth. These data show that resveratrol directly targets DDX5 and induces cancer cell death by inhibiting the mTORC1 pathway.
Highlights
Resveratrol was subsequently reported to activate sirtuin 1 by directly inhibiting phosphodiesterases (PDEs)[17] and has recently been suggested again to directly activate sirtuin 1.18
It was reported that AMPK inhibited the mammalian target of rapamycin complex 1 (mTORC1) pathway,[26] which promotes the development of prostate cancer,[23] and that resveratrol inhibited the mTORC1 pathway.[7,39]
Carboxylase (ACC) at Ser[79] (Figure 1b), indicating the activation of AMPK, only resveratrol inhibited the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) at Thr[389] and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), reflecting the activation of mTORC1 (Figure 1c). These results suggest that resveratrol suppresses the mTORC1 pathway and growth of prostate cancer cells independent of the inhibition of PDE
Summary
Resveratrol was subsequently reported to activate sirtuin 1 by directly inhibiting phosphodiesterases (PDEs)[17] and has recently been suggested again to directly activate sirtuin 1.18 Regardless of this controversy, these direct target molecules such as sirtuin 1 and PDEs cannot sufficiently account for other diverse molecular actions of resveratrol. Resveratrol modulates multiple signaling pathways, for example, by inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway.[13,20] The mTORC1 pathway is known to be deregulated in various human diseases, such as malignant tumors, obesity, type II diabetes, and neurodegenerative diseases.[21] Especially in malignancies, mTORC1 signaling promotes growth, survival, invasion, metastasis, and angiogenesis,[22,23] and mTORC1 inhibitors are used for cancer therapy.[21] mTORC1 signaling is regulated by divergent pathways and molecules, such as the phosphatidylinositol 3-kinase pathway,[24] mitogen-activated protein kinase pathway,[25] AMP-activated protein kinase (AMPK) pathway,[26] and astrin.[27] the regulation of the mTORC1 pathway has yet to be clarified and elucidating this will contribute to the development of novel strategies to treat various diseases. DDX5 promotes growth,[33] metastasis,[34] and drug resistance[35] by activating several oncogenic pathways.[34,36] DDX5 functions as a transcriptional co-activator of the androgen receptor in hormone-dependent prostate cancer,[37] its roles in hormone-independent prostate cancer have not been clarified
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
