Fatty-Acid Receptor CD36 Functions As a Hydrogen Sulfide-Targeting Receptor with Its Cys333-Cys272 Disulfide Bond Serving As a Specific Molecular Switch to Accelerate Gastric Cancer Metastasis

Background: There is a large body of evidence suggesting that hydrogen sulfide (H2S) plays an important role in cancer metastasis; however, the molecular mechanisms of H2S-mediated acceleration of cancer metastasis remain unknown. Methods: We used RNA-sequencing to identify potential differences in gene expression in vitro. Using mass spectrometry, we identified a disulfide complex within CD36 that was labile to H2S-mediated modification. Targeting CD36 in vivo blocked H2S-promoted gastric cancer (GC) metastasis and improved animal survival. Tumor 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 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. Interpretation: CD36 gene transcription and CD36 subcellular recycling formed a positive feedback loop, and this disulfide bond within CD36 acted as a special molecular for this positive feedback. H2S opened the switch and induced LC-FA-mediated signaling, thus accelerating the metastasis of GC. Genetic and pharmacological blockade of CD36 function could be harnessed as an anti-metastasis therapeutic strategy. Therefore, we propose an effective strategy for anti-metastasis by blocking CD36. Funding: This work was supported by the Strategic Priority Research Program of the Science and Technology Commission of Shanghai (1312JC1408402 for Zhirong Wang). Declaration of Interest: All authors have no potential conflicts of interest. Ethical Approval: This animal study was conducted in accordance with the rules and regulations of the Institutional Animal Care and Use Committee (IACUC) at the Department of Laboratory Animal Science, Fudan University (Shanghai, P.R. China). Informed consent was approved by the Ethics Committees of Tongji Hospital and all subjects gave written informed consent.