1. Academic Validation
  2. Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation

Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation

  • Chem Biol Interact. 2023 May 31;110588. doi: 10.1016/j.cbi.2023.110588.
Xinyu Qian 1 Lin Zhu 2 Mengzhen Xu 2 Haoli Liu 2 Xinyan Yu 2 Qiuyue Shao 2 Jing Qin 3
Affiliations

Affiliations

  • 1 Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine (Hangzhou Cancer Hospital), Hangzhou, Zhejiang, 310006, China.
  • 2 Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
  • 3 Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic oncology (lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, 310022, PR China. Electronic address: qinjing@zjcc.org.cn.
Abstract

Small cell lung Cancer (SCLC) is a subtype of lung Cancer with a very poor overall survival rate due to its extremely high proliferation and metastasis predilection. Shikonin is an active ingredient extracted from the roots of Lithospermum erythrorhizon, and exerts multiple anti-tumor functions in many cancers. In the present study, the role and underlying mechanism of shikonin in SCLC were investigated for the first time. We found that shikonin effectively suppressed cell proliferation, Apoptosis, migration, invasion, and colony formation and slightly induced Apoptosis in SCLC cells. Further experiment indicated the shikonin could also induced Ferroptosis in SCLC cells. Shikonin treatment effectively suppressed the activation of ERK, the expression of Ferroptosis inhibitor GPX4, and elevated the level of 4-HNE, a biomarker of Ferroptosis. Both total ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment. More importantly, our data identified that the function of shikonin was dependent on the up-regulation of ATF3 by performing rescue experiments using shRNA to silence the expression of ATF3, especially in the total and lipid ROS accumulaiton. Xenograft model was established using SBC-2 cells, and the results revealed that shikonin also significantly inhibited tumor growth by inducing Ferroptosis. Finally, our data further confirmed that shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-Myc on the ATF3 promoter, and subsequently elevating of histone acetylation. Our data documented that shikonin suppressed SCLC by inducing Ferroptosis in a ATF3-dependent manner. Shikonin upregulated the expression of ATF3 expression via promoting the histone acetylation by inhibiting c-myc-mediated HDAC1 binding on ATF3 promoter.

Keywords

ATF3; Ferroptosis; Histone acetylation; ROS; Shikonin; Small cell lung cancer.

Figures
Products