Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12474-9. doi: 10.1073/pnas.1306241110. Epub 2013 Jul 8.
The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target.
硫化氢 (H2S) 的生理功能包括血管舒张、刺激细胞生物能学和促进血管生成。对人类结肠癌活检组织和患者匹配的正常边缘黏膜的分析表明，H2S 产生酶胱硫醚-β-合酶 (CBS) 在结肠癌中选择性上调，导致 H2S 产生率增加。同样，与非恶性结肠黏膜细胞 NCM356 相比，结肠癌衍生的上皮细胞系 (HCT116、HT-29、LoVo) 表现出选择性 CBS 上调和 H2S 产生增加。CBS 定位于细胞质和线粒体外膜。通过 shRNA 介导的 CBS 沉默或其药理学抑制剂氨基氧乙酸 (AOA) 降低了 HCT116 细胞的增殖、迁移和侵袭；减少了肿瘤/内皮细胞共培养物中内皮细胞的迁移；并抑制了线粒体功能（耗氧量、ATP 周转率和呼吸储备能力）以及糖酵解。用氨基氧乙酸处理裸鼠可减弱患者来源的结肠癌异种移植物的生长并减少肿瘤血流。同样，肿瘤细胞中 CBS 的沉默降低了异种移植物的生长并抑制了新血管密度，表明内源性 H2S 在肿瘤血管生成中起作用。与 CBS 相反，胱硫醚-γ-裂合酶的沉默（其在结肠癌中的表达不变）不影响肿瘤生长或生物能学。总之，CBS 产生的 H2S 用于 (i) 维持结肠癌细胞生物能学，从而支持肿瘤生长和增殖，和 (ii) 促进血管生成和血管舒张，从而为肿瘤提供血液和营养物质。目前的发现将 CBS 衍生的 H2S 确定为肿瘤生长因子和抗癌药物靶点。
