Oncotarget

Research Papers:

SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes

Youn Kyung Choi, Sung-Gook Cho, Yu-Jeong Choi, Yee Jin Yun, Kang Min Lee, Kangwook Lee, Hye-Hyun Yoo, Yong Cheol Shin and Seong-Gyu Ko _

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Oncotarget. 2017; 8:88386-88400. https://doi.org/10.18632/oncotarget.11393

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Abstract

Youn Kyung Choi1,*, Sung-Gook Cho2,*, Yu-Jeong Choi3, Yee Jin Yun3, Kang Min Lee4, Kangwook Lee4, Hye-Hyun Yoo5, Yong Cheol Shin6 and Seong-Gyu Ko6

1Jeju International Marine Science Center for Research and Education, Korea Institute of Ocean Science and Technology (KIOST), Jeju, 695-975, Korea

2Department of Biotechnology, Korea National University of Transportation, Chungbuk, 368-701, Korea

3Department of Cancer Preventive Material Development, Graduate School, Kyung Hee University, Seoul, 130-701, Korea

4Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 130-701, Korea

5Institute of Pharmaceutical Science and Technology and Collage of Pharmacy, Hanyang University, Gyonggi, 426-791, Korea

6Laboratory of Clinical Biology and Pharmacogenomics, Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Korea

*These authors contributed equally to this work

Correspondence to:

Seong-Gyu Ko, email: epiko@khu.ac.kr

Keywords: SH003, breast cancer, autophagy, apoptosis, p62

Received: October 15, 2015     Accepted: July 27, 2016     Published: August 19, 2016

ABSTRACT

Drug markets revisits herbal medicines, as historical usages address their therapeutic efficacies with less adverse effects. Moreover, herbal medicines save both cost and time in development. SH003, a modified version of traditional herbal medicine extracted from Astragalus membranaceus (Am), Angelica gigas (Ag), and Trichosanthes Kirilowii Maximowicz (Tk) with 1:1:1 ratio (w/w) has been revealed to inhibit tumor growth and metastasis on highly metastatic breast cancer cells, both in vivo and in vitro with no toxicity. Meanwhile, autophagy is imperative for maintenance cellular homeostasis, thereby playing critical roles in cancer progression. Inhibition of autophagy by pharmacological agents induces apoptotic cell death in cancer cells, resulting in cancer treatment. In this study, we demonstrate that SH003-induced autophagy via inhibiting STAT3 and mTOR results in an induction of lysosomal p62/SQSTM1 accumulation-mediated reactive oxygen species (ROS) generation and attenuates tumor growth. SH003 induced autophagosome and autolysosome formation by inhibiting activation of STAT3- and mTOR-mediated signaling pathways. However, SH003 blocked autophagy-mediated p62/SQSTM1 degradation through reducing of lysosomal proteases, Cathepsins, resulting in accumulation of p62/SQSTM1 in the lysosome. The accumulation of p62/SQSTM1 caused the increase of ROS, which resulted in the induction of apoptotic cell death. Therefore, we conclude that SH003 suppresses breast cancer growth by inducing autophagy. In addition, SH003-induced p62/SQSTM1 could function as an important mediator for ROS generation-dependent cell death suggesting that SH003 may be useful for treating breast cancer.


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