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Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer.
Proc Natl Acad Sci U S A. 2013 Jul 23; 110(30):12474-9.PN

Abstract

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.

Authors+Show Affiliations

Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA. szabocsaba@aol.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23836652

Citation

Szabo, Csaba, et al. "Tumor-derived Hydrogen Sulfide, Produced By Cystathionine-β-synthase, Stimulates Bioenergetics, Cell Proliferation, and Angiogenesis in Colon Cancer." Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 30, 2013, pp. 12474-9.
Szabo C, Coletta C, Chao C, et al. Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci U S A. 2013;110(30):12474-9.
Szabo, C., Coletta, C., Chao, C., Módis, K., Szczesny, B., Papapetropoulos, A., & Hellmich, M. R. (2013). Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(30), 12474-9. https://doi.org/10.1073/pnas.1306241110
Szabo C, et al. Tumor-derived Hydrogen Sulfide, Produced By Cystathionine-β-synthase, Stimulates Bioenergetics, Cell Proliferation, and Angiogenesis in Colon Cancer. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12474-9. PubMed PMID: 23836652.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. AU - Szabo,Csaba, AU - Coletta,Ciro, AU - Chao,Celia, AU - Módis,Katalin, AU - Szczesny,Bartosz, AU - Papapetropoulos,Andreas, AU - Hellmich,Mark R, Y1 - 2013/07/08/ PY - 2013/7/10/entrez PY - 2013/7/10/pubmed PY - 2013/10/18/medline SP - 12474 EP - 9 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 110 IS - 30 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/23836652/Tumor_derived_hydrogen_sulfide_produced_by_cystathionine_β_synthase_stimulates_bioenergetics_cell_proliferation_and_angiogenesis_in_colon_cancer_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=23836652 DB - PRIME DP - Unbound Medicine ER -