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PNAS:臭鸡蛋与结肠癌

来源:生物谷 2013-07-09 17:34

2013年7月10日讯 /生物谷BIOON/--德克萨斯大学科学家发现具有臭鸡蛋气味的硫化氢是结肠癌细胞代谢过程中的重要元件,该物质有望成为治疗结肠癌的靶点。相关报道发表在最近一期PNAS杂志上。

研究人员在细胞培养和小鼠模型中证明了结肠癌细胞能够产生大量的硫化氢,并依赖硫化氢生存和生长。

该文章的作者Csaba Szabo博士称,结肠癌细胞渴望该物质,我们的结果显示结肠癌细胞采用硫化氢来制造能量,分化以及生长。

研究人员称结肠癌中制造硫化氢的蛋白为CBS,实验表明当CBS活性被化学阻断后,结肠癌细胞生长变缓,而正常细胞生长不受影响。

该文章的作者Mark Hellmich教授称,我们的工作表明CBS是一个新的抗癌靶点,通过阻断CBS,能够对抗结肠癌。

科学家在移植结肠癌细胞的裸鼠中同样得到了类似的效果,阻断CBS能够对抗结肠癌。当硫化氢消失后,癌细胞生长非常缓慢,而且肿瘤周围的血管生成过程也变得缓慢。

该发现令Szabo博士感到惊讶,回顾进化历史,Szabo博士又表示该发现是有意义的。在数十亿年以前,地球上还没有氧气的时候,硫化氢就是支持生物体的主要物质,Szabo博士称,结肠癌通过产生硫化氢重建了古老的生存机制。(生物谷Bioon.com)

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Csaba Szabo, Ciro Coletta, Celia Chao, Katalin Módis, Bartosz Szczesny, Andreas Papapetropoulos, and Mark R. Hellmich

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.

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