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- Title
Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo.
- Authors
Liu, Xuejiao; Song, Mengqiu; Wang, Penglei; Zhao, Ran; Chen, Hanyong; Zhang, Man; Shi, Yuanyuan; Liu, Kangdong; Liu, Fangfang; Yang, Ran; Li, Enmin; Bode, Ann M.; Dong, Zigang; Lee, Mee‐Hyun
- Abstract
Esophageal cancer, a leading cause of cancer death worldwide, is associated with abnormal activation of the AKT signaling pathway. Xanthohumol, a prenylated flavonoid tested in clinical trials, is reported to exert anti‐diabetes, anti‐inflammation and anticancer activities. However, the mechanisms underlying its chemopreventive or chemotherapeutic effects remain elusive. In the present study, we found that xanthohumol directly targeted AKT1/2 in esophageal squamous cell carcinoma (ESCC). Xanthohumol significantly inhibited the AKT kinase activity in an ATP competitive manner, which was confirmed in binding and computational docking models. KYSE70, 450 and 510 ESCC cell lines highly express AKT and knockdown of AKT1/2 suppressed proliferation of these cells. Treatment with xanthohumol inhibited ESCC cell growth and induced apoptosis and cell cycle arrest at the G1 phase. Xanthohumol also decreased expression of cyclin D1 and increased the levels of cleaved caspase‐3, ‐7 and ‐PARP as well as Bax, Bims and cytochrome c in ESCC cells by downregulating AKT signaling targets, including glycogen synthase kinase 3 beta (GSK3β), mammalian target of rapamycin, and ribosomal protein S6 (S6K). Furthermore, xanthohumol decreased tumor volume and weight in patient‐derived xenografts (PDXs) that highly expressed AKT, but had no effect on PDXs that exhibited low expression of AKT in vivo. Kinase array results showed that xanthohumol treatment decreased phosphorylated p27 expression in both ESCC cell lines and PDX models. Taken together, our data suggest that the inhibition of ESCC tumor growth with xanthohumol is caused by targeting AKT. These results provide good evidence for translation toward clinical trials with xanthohumol. What's new? Esophageal squamous cell carcinoma (ESCC) is among the most common and deadliest forms of esophageal malignancy. Chemotherapy remains the mainstay of treatment, even though many ESCC patients experience disease progression despite therapy. Here, the authors investigated a novel agent for ESCC, the prenylated flavonoid xanthohumol. In ESCC cells, xanthohumol was found to directly target AKT kinase, inhibiting AKT activity, suppressing cell proliferation, and inducing apoptosis. In a patient‐derived xenograft mouse model, xanthohumol reduced tumor volume specifically in high AKT‐expressing tumors, with little effect on low AKT tumors. The data suggest that AKT targeting is a promising therapeutic strategy in ESCC.
- Subjects
SQUAMOUS cell carcinoma; CELL growth; GLYCOGEN synthase kinase; RIBOSOMAL proteins; THERAPEUTICS; CELL proliferation
- Publication
International Journal of Cancer, 2019, Vol 145, Issue 4, p1007
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.32285