Xanthohumol Inhibits the Growth of Keratin 18-Overexpressed Esophageal Squamous Cell Carcinoma in vitro and in vivo.

Shuying Yin,Ran Zhao,Xuejiao Liu,Woo Kyu Kang,Kangdong Liu,Jeong Min Lee,Mee-Hyun Lee,Zigang Dong,Chengjuan Zhang,Young Eun Kim,Jung-Hyun Shim,Mengqiu Song

doi:10.3389/fcell.2020.00366

Abstract

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death worldwide. Xanthohumol is a prenylated flavonoid isolated from hops. Although xanthohumol has been reported to exert anti-obesity, hypoglycemic, anti-hyperlipidemia and anti-cancer activities, the mechanisms underlying its chemotherapeutic activity are yet to be elucidated. In the present study, we found that xanthohumol inhibited ESCC cell proliferation in vitro and in vivo by targeting keratin (KRT)-18. Xanthohumol suppressed the proliferation, foci formation, and anchorage-independent colony growth of KYSE30 cells. Using xanthohumol-sepharose conjugated bead pull-down and mass/mass analysis, we found that KRT18 is a novel target of xanthohumol in KYSE30 cells. KRT18 protein was highly expressed in patient ESCC tissues compared to adjunct tissues. Anti-proliferative activity of xanthohumol was abrogated or enhanced according to the knockdown or overexpression of KRT18 protein, respectively. Xanthohumol also induced apoptosis and cell cycle arrest at G1 phase which was associated with the modulation of expression of related makers including cyclin D1, cyclin D3, and cleaved-PARP, Bcl-2, cytochrome c and Bax. While xanthohumol attenuated KRT18 protein expression, it failed to cause any change in the KRT18 mRNA level. Furthermore, oral administration of xanthohumol decreased tumor volume and weight in patient-derived xenografts (PDXs) tumors having overexpressed KRT18. Overall these results suggest that xanthohumol acts as a KRT18 regulator to suppress the growth of ESCC.

Highlights

Esophageal cancer (EC) is the ninth leading cause of cancer-related death worldwide
A number of Food and Drug Administration (FDA) approved therapies, such as growth factor receptor inhibitors and immunotherapies are currently used in clinical settings, none of these therapies are uniformly effective in all patient groups
It has been reported that xanthohumol inhibits colorectal cancer cells via downregulation of Hexokinases II-mediated glycolysis (Liu W. et al, 2019; Logan et al, 2019), exhibits anti-myeloma activity in vitro through inhibition of cell proliferation via the ERK and JNK-dependent mechanism (Slawinska-Brych et al, 2019) and exerts anticancer effects against gastric cancer (Wei et al, 2018)

Summary

Introduction

Esophageal cancer (EC) is the ninth leading cause of cancer-related death worldwide. EC patients always have poor prognosis with 5-year survival rate about 19% (Bray et al, 2018; Siegel et al, 2019). Food and Drug Administration (FDA)-approved 13 drugs for EC treatment, many of these are targeted therapies such as cetuximab and lapatinib (targeting epidermal growth factor receptor, EGFR), irinotecan (inhibitor of type I topoisomerase), trastuzumab (monoclonal antibody against human epidermal growth factor receptor 2, HER2) and apitinib (inhibitor of vascular endothelial growth factor, VEGFR) (Teicher, 2008; Davidson and Starling, 2016; Huang et al, 2018; Barsouk et al, 2019) These drugs have failed to reach clinical success to curb EC prevalence largely due to non-responsiveness of many patients. There is emerging need for developing new therapies with better efficacy and tolerability by focusing on novel drug targets

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