Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells

Chen, Pengchen1,2,3,4; Zhong, Xiaoru1,2,3,4; Song, Yali5; Zhong, Wenbin5; Wang, Sisi1,2,3,4; Wang, Jinyan1,2,3,4; Huang, Pan1,2,3,4; Niu, Yaping1,2,3,4; Yang, Wenyue6; Ding, Ziyang1,2,3,4; Luo, Qingming5; Yang, Chuanbin1,2,3,4; Wang, Jigang1,2,3,4,5,6,7,8; Zhang, Wei1,2,3,4

2024-04-10

10.1016/j.canlet.2024.216622

CANCER LETTERS   影响因子和分区

0304-3835

1872-7980

Triptolide, a natural bioactive compound derived from herbal medicine Tripterygium wilfordii, has multiple biological activities including anti-cancer effect, which is being tested in clinical trials for treating cancers. However, the exact mechanism by which Triptolide exerts its cytotoxic effects, particularly its specific protein targets, remains unclear. Here, we show that Triptolide effectively induces cytotoxicity in gastric cancer cells by increasing reactive oxygen species (ROS) levels. Further investigations reveal that ROS accumulation contributes to the induction of Endoplasmic Reticulum (ER) stress, and subsequently autophagy induction in response to Triptolide. Meanwhile, this autophagy is cytoprotective. Interestingly, through activity-based protein profiling (ABPP) approach, we identify peroxiredoxins-2 (PRDX2), a component of the key enzyme systems that act in the defense against oxidative stress and protect cells against hydroperoxides, as direct binding target of Triptolide. By covalently binding to PRDX2 to inhibit its antioxidant activity, Triptolide increases ROS levels. Moreover, overexpression of PRDX2 inhibits and knockdown of the expression of PRDX2 increases Triptolide-induced apoptosis. Collectively, these results indicate PRDX2 as a direct target of Triptolides for inducing apoptosis. Our results not only provide novel insight into the underlying mechanisms of Triptolide-induced cytotoxic effects, but also indicate PRDX2 as a promising potential therapeutic target for developing anti-gastric cancer agents.

Gastric cancer Triptolide Endoplasmic reticulum stress Autophagy Peroxiredoxin-2

SCI

英语

通讯

Guangdong-Dongguan Joint Fund Regional Cultivation Project[2021B1515140033] ; Dongguan Science and Technology of Social Development Program[20221800905732]

Oncology

Oncology

WOS:001197386400001

ELSEVIER IRELAND LTD

CLINICAL MEDICINE

Web of Science

1.Shenzhen Peoples Hosp, Shenzhen Inst Resp Dis, Dept Pulm & Crit Care Med, Shenzhen 518020, Peoples R China
2.Shenzhen Peoples Hosp, Shenzhen Clin Res Ctr Geriatr, Shenzhen 518020, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
4.Jinan Univ, Clin Med Coll 2, Shenzhen 518020, Peoples R China
5.Southern Med Univ, Dongguan Maternal & Child Hlth Care Hosp, Postdoctoral Innovat Practice Base, Dongguan 523125, Guangdong, Peoples R China
6.Guangdong Pharmaceut Univ, Chinese Med Res Inst, Guangzhou 510006, Guangdong, Peoples R China
7.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
8.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China

Chen, Pengchen,Zhong, Xiaoru,Song, Yali,et al. Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells[J]. CANCER LETTERS,2024,587.

Chen, Pengchen.,Zhong, Xiaoru.,Song, Yali.,Zhong, Wenbin.,Wang, Sisi.,...&Zhang, Wei.(2024).Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells.CANCER LETTERS,587.

Chen, Pengchen,et al."Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells".CANCER LETTERS 587(2024).