The Antitumor Effect of Caffeic Acid Phenethyl Ester by Downregulating Mucosa-Associated Lymphoid Tissue 1 via AR/p53/NF-κB Signaling in Prostate Carcinoma Cells
by
,
Kang-Shuo Chang
1,†, 
Ke-Hung Tsui
2,3,†,
Shu-Yuan Hsu
1,4,
Hsin-Ching Sung
1,4,
Yu-Hsiang Lin
5,
Chen-Pang Hou
5,
Pei-Shan Yang
5,
Chien-Lun Chen
5, 
Tsui-Hsia Feng
6 and
Horng-Heng Juang
1,4,5,* 1
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
2
Department of Urology, Shuang Ho Hospital, New Taipei City 235041, Taiwan
3
TMU Research Center of Urology and Kidney, Department of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
5
Department of Urology, Chang Gung Memorial Hospital-Linkou, Kwei-Shan, Taoyuan 33302, Taiwan
6
School of Nursing, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 33302, Taiwan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(2), 274; https://doi.org/10.3390/cancers14020274
Submission received: 9 December 2021
/
Revised: 29 December 2021
/
Accepted: 5 January 2022
/
Published: 6 January 2022
(This article belongs to the Special Issue Targeting the Vulnerabilities of Oncogene Activation)
Simple Summary
The effect of caffeic acid phenethyl ester (CAPE) on prostate cancer has not been thoroughly explored. CAPE downregulated the expression of androgen receptor (AR) and mucosa-associated lymphoid tissue 1 (MALT1) but enhanced that of p53, thus decreasing androgen-induced activation of MALT1 and prostate-specific antigen expressions in AR-positive prostate carcinoma cells. CAPE inhibited the activity of NF-κB in p53- and AR-negative prostate carcinoma cells. Although CAPE induced the ERK/JNK/p38/AMPKα1/2 signaling pathways, pretreatment with the corresponding inhibitors of MAPK or AMPK1/2 did not inhibit the CAPE effect on MALT1 blocking. Our results reveal that CAPE blocks the expression of the MALT1 gene to decrease the cell proliferation, invasion, and tumor growth of prostate carcinoma cells via the p53 and NF-κB signaling pathways, and they further verify that CAPE is an effective antitumor agent for human androgen-dependent and -independent prostate carcinoma cells by inhibiting MALT1 expression in vitro and in vivo.
Abstract
Caffeic acid phenethyl ester (CAPE), a honeybee propolis-derived bioactive ingredient, has not been extensively elucidated regarding its effect on prostate cancer and associated mechanisms. The mucosa-associated lymphoid tissue 1 gene (MALT1) modulates NF-κB signal transduction in lymphoma and non-lymphoma cells. We investigated the functions and regulatory mechanisms of CAPE in relation to MALT1 in prostate carcinoma cells. In p53- and androgen receptor (AR)-positive prostate carcinoma cells, CAPE downregulated AR and MALT1 expression but enhanced that of p53, thus decreasing androgen-induced activation of MALT1 and prostate-specific antigen expressions. p53 downregulated the expression of MALT in prostate carcinoma cells through the putative consensus and nonconsensus p53 response elements. CAPE downregulated MALT1 expression and thus inhibited NF-κB activity in p53- and AR-negative prostate carcinoma PC-3 cells, eventually reducing cell proliferation, invasion, and tumor growth in vitro and in vivo. CAPE induced the ERK/JNK/p38/AMPKα1/2 signaling pathways; however, pretreatment with the corresponding inhibitors of MAPK or AMPK1/2 did not inhibit the CAPE effect on MALT1 blocking in PC-3 cells. Our findings verify that CAPE is an effective antitumor agent for human androgen-dependent and -independent prostate carcinoma cells in vitro and in vivo through the inhibition of MALT1 expression via the AR/p53/NF-κB signaling pathways.
