The yes-associated protein 1 (YAP) is a nuclear downstream effector of Hippo pathway that plays a critical role in various cancers. Literature shows that, in addition to nucleus, YAP also localizes in cytosol and membrane of cells. We and our collaborators previously reported that elevation of YAP associates with Arf in the genetically-engineered mouse (GEM) model of Pten/Trp53, implicating the possible correlation between Hippo/YAP and ARF in human cancers. We recently found ARF is indeed involved in dysregulation of Hippo pathway in prostate cancer. In details, ARF inhibited nuclear YAP translocation in cancer cells, and ARF knockdown suppressed the stability of YAP protein with upregulated active AKT and dysregulated phosphorylation of YAP through ARF/AKT/mTOR/YAP pathway. Here we further report that carbon nanodots (c-dots) can induce DNA damage through an increase of ROS by upregulation of γH2AX and DNA tails in PC3 and DU145 prostate cancer cells. We found that c-dots derived from natural products such as tea or beet can enter into cancer cell nucleus to interact with ARF for the regulation of the ARF-mediated signaling such as the nuclear translocation of YAP. Mechanistically, c-dots bind ARF to induce cell cycle arrest, apoptosis, and PARP cleavage in prostate cancer cells. Most importantly, addition of c-dots into cultured PC3 cells leads to the reversal of drug resistance to mTOR inhibitor Rapamycin and MET inhibitor Crizotinib by enhancing DNA damage. Moreover, c-dots suppress the tumor size and growth of PC3 cells in xenograft mouse model in vivo. Our data suggest that the nano-scale of c-dots derived from natural food may be efficient in overcoming drug resistance via augmentation of DNA damage linked cell death. Thus we reported a new approach of abolishing drug resistance of aggressive malignancy using nanoparticles, implicating an innovative avenue for precision cancer treatment.

Citation Format: Ayan A. Nurkesh, Mannix P. Balanay, Tleubek Yeleusizov, Darkhan Tursynkhan, Qing Yang, Xiaoling Wan, Limara Manarbek, Aisulu Maipas, Bakhyt Matkarimov, Yan Zhang, Haiyan Fan, Li-Xia Miao, Si-Pian Li, Zhenbang Chen, Yingqiu Xie. Natural product-derived carbon nanodots overcome drug resistance through regulation of Hippo pathway effectors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5498.