TY - JOUR T1 - Antagonizing SET augments the effects of radiotherapy in hepatocellular carcinoma through reactivating PP2A-mediated AKT downregulation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.249102 SP - jpet.118.249102 AU - Chao-Yuan Huang AU - Man-Hsin Hung AU - Chi-Ting Shih AU - Feng-Shu Hsieh AU - Chiung-Wen Kuo AU - Ming-Hsien Tsai AU - Shih-Shin Chang AU - Yung-Jen Hsiao AU - Li-Ju Chen AU - Tzu-I Chao AU - Kuen-Feng Chen Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/06/18/jpet.118.249102.abstract N2 - Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiotherapy (RT)-mediated anti-cancer effects has not yet been explored. Here, we investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assay, we found that RT-induced proliferative inhibition was critically associated with SET expression. Next, we tested a novel SET antagonist, EMQA, in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared to mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore PP2A-mediated p-AKT downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET, and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach. ER -