Caffeic acid phenethyl ester inhibits the growth of bladder carcinoma cells by upregulating growth differentiation factor 15

Chen-Pang Hou; Ke-Hung Tsui; Kang-Shuo Chang; Hsin-Ching Sung; Shu-Yuan Hsu; Yu-Hsiang Lin; Pei-Shan Yang; Chien-Lun Chen; Tsui-Hsia Feng; Horng-Heng Juang

doi:10.1016/j.bj.2021.10.006

Caffeic acid phenethyl ester inhibits the growth of bladder carcinoma cells by upregulating growth differentiation factor 15

Biomed J. 2022 Oct;45(5):763-775. doi: 10.1016/j.bj.2021.10.006. Epub 2021 Oct 15.

Authors

Affiliations

¹ Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
² Department of Urology, Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medicine; TMU Research Center of Urology and Kindey, College of Medicine, Taipei Medical University, Taipei, Taiwan.
³ Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁵ Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
⁶ Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: hhj143@mail.cgu.edu.tw.

Abstract

Background: Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, has beneficial effects on cancer prevention. Growth differentiation factor 15 (GDF15) is an antitumor gene of bladder cancer. Therefore, this study investigated the anti-cancer effect of CAPE on bladder carcinoma cells and related mechanisms.

Methods: The expressions of GDF15, N-myc downstream-regulated gene 1 (NDRG1), and maspin, and the activations of extracellular signal regulated kinase (ERK), c-jun Nterminal kinase (JNK), p38, and 50 adenosine monophosphate-activated protein kinase (AMPK) α1/2 in human bladder cells after gene transfection or knockdown were determined by immunoblot, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), and reporter assays. The assays of 5-ethynyl-2'-deoxyuridine (EdU), CyQUANT cell proliferation, and Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis.

Results: GDF15 expression in epithelial cells was negatively correlated with neoplasia in vitro. Also, GDF15 exhibits in bladder fibroblasts and smooth muscle cells. CAPE-induced expressions of NDRG1 and maspin decreased cell proliferation and invasion of bladder carcinoma cells in a GDF15-dependent manner in vitro. The xenograft animal study suggesting CAPE attenuated tumor growth in vivo. CAPE increased phosphorylation of ERK, JNK, p38, and AMPKα1/2 to modulate the GDF15 expressions. Pretreatments with ERK, JNK, or p38 inhibitors partially inhibited the CAPE effects on the inductions of GDF15, NDRG1, or maspin. Knockdown of AMPKα1/2 attenuated the CAPE-induced GDF15 expression and cell proliferation in bladder carcinoma cells.

Conclusions: Our findings indicate that CAPE is a promising agent for anti-tumor growth in human bladder carcinoma cells via the upregulation of GDF15.

Keywords: AMPK; Bladder; CAPE; GDF15; MAPK; NDRG1.

MeSH terms

Animals
Carcinoma* / pathology
Cell Line, Tumor
Epithelial Cells
Gene Expression Regulation, Neoplastic
Growth Differentiation Factor 15 / genetics
Humans
Urinary Bladder / pathology
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / genetics
Urinary Bladder Neoplasms* / pathology

Substances

caffeic acid phenethyl ester
Growth Differentiation Factor 15