Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasisResearch in context
Rui Wang,
Beibei Tao,
Qilin Fan,
Shengyue Wang,
Li Chen,
Junjie Zhang,
Yinfang Hao,
Shuang Dong,
Zhe Wang,
Wei Wang,
Yixi Cai,
Xutong Li,
Tuvshin Bao,
Xiaohui Wang,
Xiaoming Qiu,
Kekun Wang,
Xinyu Mo,
Yuqi Kang,
Zhirong Wang
Affiliations
Rui Wang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Beibei Tao
Department of Physiology and Pathophysiology, School of Basic Medicine, Fudan University, Shanghai 200032, China
Qilin Fan
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Shengyue Wang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Li Chen
Department of Gastroenterology, Baoshan Branch, Renji Hospital, Affiliated to Shanghai Jiaotong University, Shanghai 200444, China
Junjie Zhang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Yinfang Hao
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Shuang Dong
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Zhe Wang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Wei Wang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China
Yixi Cai
Department of Pediatrics, First People's Hospital of Liangjiang New District, Chongqing 401121, China
Xutong Li
Department of Neurology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Tuvshin Bao
Department of Anesthesia, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Xiaohui Wang
Department of Pancreatic Surgery, State Key Laboratory of Oncology in South China, Zhongshan University, Guangzhou 510001, China
Xiaoming Qiu
Department of Orthopedics, Provincial Hospital of Gansu Province, Lanzhou 730001, China
Kekun Wang
School of Health Science, Wuhan University, Wuhan 430030, China
Xinyu Mo
First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300001, China
Yuqi Kang
Department of Oncology, Oncology Hospital of Guizhou Province, Guiyang 550001, China
Zhirong Wang
Department of Gastroenterology, Tongji Hospital, Affiliated to Tongji University, Shanghai 200065, China; Corresponding author at: Department of Gastroenterology, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, China.
Background: Hydrogen Sulfide (H2S), a third member of gasotransmitter family along with nitric oxide (NO) and carbon monoxide (CO), exerts a wide range of cellular and molecular actions in our body. There is a large body of evidence suggesting that H2S plays an important role in cancer metastasis; however, the molecular mechanisms of H2S-mediated acceleration of cancer metastasis remain unknown. Methods: We examined the promote effects of H2S on phenotype of gastric cancer (GC) cells (including those of express wild type CD36 and mutant CD36) in vitro and in vivo. GC patients' samples were used for clinical translational significance evaluation. Findings: H2S triggered lipid metabolism reprogramming by significantly up-regulating the expression of the fatty-acid receptor CD36 (CD36) and directly activating CD36 in GC cells. Mechanistically, a disulfide bond located between cysteine (Cys)333 and Cys272 within the CD36 protein structure that was labile to H2S-mediated modification. The long chain-fatty acid (LC-FA) binding pocket was capped by a turn in the CD36 protein, located between helical and sheet structures that were stabilized by the Cys333-Cys272. This limited the secondary binding between LC-FAs and lysine (Lys)334. Breaking the Cys333-Cys272 disulfide bond restored the second LC-FA binding conformation of CD36. Targeting CD36 in vivo blocked H2S-promoted metastasis and improved animal survival. Interpretation: These findings identify that the Cys333-Cys272 disulfide bond disrupted the integrity of the second LC-FA binding conformation of CD36. Therefore, CD36 can directly activate LC-FA access to the cytoplasm by acting as a direct target molecule for H2S. Keywords: H2S, CD36, Disulfide bond, Long chain-fatty acid, Nrf2, Metastasis
