| First Author | Yongxi T | Year | 2015 |
| Journal | Biochem Biophys Res Commun | Volume | 465 |
| Issue | 3 | Pages | 494-500 |
| PubMed ID | 26278819 | Mgi Jnum | J:232885 |
| Mgi Id | MGI:5780379 | Doi | 10.1016/j.bbrc.2015.08.045 |
| Citation | Yongxi T, et al. (2015) Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular carcinoma cell activity in vitro and in vivo. Biochem Biophys Res Commun 465(3):494-500 |
| abstractText | Recent studies have indicated that mammalian target of rapamycin (mTOR) signaling has a critical role in the pathogenesis of hepatocellular carcinoma (HCC). In the current study, we investigated the activity of KU-0063794, a novel mTOR kinase inhibitor, against HepG2 HCC cells. Our results demonstrated that KU-0063794 blocked mTOR complex 1/2 (mTORC1/2) activation, and downregulated mTOR-regulated genes (Cyclin D1 and hypoxia-inducible factor 1alpha) in HepG2 cells. Consequently, KU-0063794 induced significant anti-survival and pro-apoptotic activities against HepG2 cells. When analyzing the possible KU-0063794-resistance factors, we showed that KU-0063794 induced cyto-protective autophagy activation in HepG2 cells, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 degradation, Beclin-1 expression and LC3B-I to LC3B-II conversion. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine (3-MA) and chloroquine, dramatically enhanced KU-0063794-induced cytotoxicity against HepG2 cells. Further, RNAi knockdown of Beclin-1 also increased KU-0063794 sensitivity in HepG2 cells. In vivo, oral administration of KU-0063794 repressed HepG2 xenograft growth in severe combined immunodeficient (SCID) mice, and its activity was further enhanced with co-administration of the autophagy inhibitor 3-MA. In summary, KU-0063794 inhibits HepG2 cell growth in vitro and in vivo, its activity could be further enhanced with autophagy inhibition. |
