Oncotarget

Research Papers:

B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy

Fang-Yuan Shao, Zhi-Yun Du, Dong-Lei Ma, Wen-Bo Chen, Wu-Yu Fu, Bi-Bo Ruan, Wen Rui, Jia-Xuan Zhang, Sheng Wang, Nai Sum Wong, Hao Xiao, Man-Mei Li, Xiao Liu, Qiu-Ying Liu, Xiao-dong Zhou, Hai-Zhao Yan, Yi-Fei Wang, Chang-Yan Chen, Zhong Liu _ and Hong-Yuan Chen

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Oncotarget. 2015; 6:30939-30956. https://doi.org/10.18632/oncotarget.5132

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Abstract

Fang-Yuan Shao1,*, Zhi-Yun Du3,*, Dong-Lei Ma2, Wen-Bo Chen2, Wu-Yu Fu1, Bi-Bo Ruan1, Wen Rui1, Jia-Xuan Zhang2, Sheng Wang2, Nai Sum Wong4, Hao Xiao5, Man-Mei Li2, Xiao Liu1, Qiu-Ying Liu2, Xiao-dong Zhou6, Hai-Zhao Yan2, Yi-Fei Wang2, Chang-Yan Chen7, Zhong Liu2, Hong-Yuan Chen1

1Department of Pathogen Biology and Immunology, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, P.R. China

2Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China

3Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China

4Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

5University of the Chinese Academy of Sciences, Beijing, China

6Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China

7Center for Drug Discovery, Northeastern University, Boston, MA, USA

*These authors have contributed equally to this work

Correspondence to:

Zhong Liu, e-mail: tliuzh@jnu.edu.cn

Hong-Yuan Chen, e-mail: hychen1208@126.com

Keywords: curcumin analog, thioredoxin reductase, cervical cancer, apoptosis

Received: March 26, 2015     Accepted: August 24, 2015     Published: September 04, 2015

ABSTRACT

The synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.


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