Diallyl trisulfide, a H₂ S donor, inhibits cell growth of human papillary thyroid carcinoma KTC-1 cells through a positive feedback loop between H₂ S and cystathionine-gamma-lyase

Diallyl trisulfide (DATS), derived from garlic, is a well-known hydrogen sulfide (H₂ S) donor. H₂ S has recently emerged as a novel gasotransmitter involved in the regulation of cancer progression. The present study demonstrated that DATS along with other two H₂ S donors, NaHS and GYY4137, significantly inhibited papillary thyroid carcinoma KTC-1 cells growth. DATS treatment triggered a rapid H₂ S generation within 5 min in KTC-1 cells. Iodoacetamide, a potent thiol blocker reagent, partially rescued the cell membrane damage and ultimate cell death induced by DATS, indicating H₂ S contributed to the apoptosis-inducing efficacy of DATS on thyroid cancer cells. Specifically, DATS treatment significantly upregulated the expression and enzymatic activity of cystathionine gamma-lyase (CTH), one of H₂ S-producing enzymes, which was responsible for endogenous H₂ S generation. After DATS treatment, H₂ S quickly permeated cell membranes and activated NF-κΒ/p65 signaling pathway in KTC-1 cells. Nuclear translocated NF-κB bound to the promoter of CTH to enhance its transcription. These evidences proved that exogenous H₂ S elevated CTH expression. CTH, in turn, catalytically generated a much higher level of endogenous H₂ S. This positive feedback sustained excess H₂ S production, which resulted in PTC cells growth inhibition. These findings may shed light on the development of novel H₂ S-based antitumor agents.