Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo

Xuejiao Liu, Mengqiu Song, Penglei Wang, Ran Zhao, Hanyong Chen, Man Zhang, Yuanyuan Shi, Kangdong Liu, Fangfang Liu, Ran Yang, Enmin Li, Ann M. Bode, Zigang Dong, Mee Hyun Lee

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1007-1019
Number of pages13
JournalInternational Journal of Cancer
Volume145
Issue number4
DOIs
StatePublished - Aug 15 2019

Bibliographical note

Funding Information:
Key words: targeting AKT kinase activity, xanthohumol, AKT signaling pathway, esophageal squamous cell carcinoma Additional Supporting Information may be found in the online version of this article. Conflict of Interest: The authors declare no conflicts of interest. *X.L., M.S. and P.W. contributed equally to this work [Correction added May 9 after first online publication: Affiliation was updated.] Grant sponsor: Key program of Henan Province, China; Grant number: 161100510300; Grant sponsor: The National Institute of Health (NIH), USA; Grant numbers: CA 196639, CA187027; Grant sponsor: The National Natural Science Foundation of China; Grant numbers: NSFC81672767, 81802875 DOI: 10.1002/ijc.32285 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. History: Received 11 Oct 2018; Accepted 12 Mar 2019; Online 18 Mar 2019. Correspondence to: Zigang Dong, The Hormel Institute, University of Minnesota, 801 16 Ave NE, Austin, MN 55912, USA, Tel.: +1-507-437-9600, Fax: +1-507-437-9606, E-mail: zgdong@hi.umn.edu; or Mee-Hyun Lee, China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan, 450008, China, Tel.: +86-371-65587008, Fax: +86-371-65587670, E-mail: mhlee@hci-cn.org; or mhyun_lee@hanmail.net

Funding Information:
We wish to thank Shen Yang, China-US (Henan) Hormel Cancer Institute for supporting experiments. This work was supported by grant funding from the National Institute of Health (NIH), USA, CA187027 and CA 196639; the Key Program of Henan Province, China, Grant No. 161100510300 (to Z. Dong); the National Natural Science Foundation of China NSFC81672767 (to M. Lee) and No. 81802875 (to X. Liu) and Henan Provincial Government, China.

Publisher Copyright:
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

Keywords

  • AKT signaling pathway
  • esophageal squamous cell carcinoma
  • targeting AKT kinase activity
  • xanthohumol

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