Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential

Eric Sonke; Megan Verrydt; Carl O Postenka; Siddika Pardhan; Chantalle J Willie; Clarisse R Mazzola; Matthew D Hammers; Michael D Pluth; Ian Lobb; Nicholas E Power; Ann F Chambers; Hon S Leong; Alp Sener

doi:10.1016/j.niox.2015.06.001

Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential

Nitric Oxide. 2015 Sep 15:49:26-39. doi: 10.1016/j.niox.2015.06.001. Epub 2015 Jun 9.

Authors

Affiliations

¹ Department of Anatomy & Cell Biology, Schulich Medicine and Dentistry, Medical Sciences Building Room 443, Western University, London, Ontario N6A 5C1, Canada; Matthew Mailing Centre for Translational Transplant Studies, 339 Windermere Rd., London Health Sciences Centre, London, Ontario N6A 5A5, Canada. Electronic address: esonke@uwo.ca.
² Matthew Mailing Centre for Translational Transplant Studies, 339 Windermere Rd., London Health Sciences Centre, London, Ontario N6A 5A5, Canada; Department of Biology, 1151 Richmond St., Western University, London, Ontario N6A 5B7, Canada. Electronic address: mverrydt@uwo.ca.
³ London Regional Cancer Program, 790 Commissioners Rd. E, London Health Sciences Centre, London, Ontario N6A 5A5, Canada. Electronic address: cpostenk@uwo.ca.
⁴ Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Translational Prostate Cancer Research Laboratory, F3-124, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada. Electronic address: siddika.15@gmail.com.
⁵ Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Translational Prostate Cancer Research Laboratory, F3-124, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada. Electronic address: chantalle.willie@gmail.com.
⁶ Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada. Electronic address: mazzola_clarisse@hotmail.fr.
⁷ Department of Chemistry & Biochemistry, 1253 University of Oregon, University of Oregon, Eugene, OR 97403, USA. Electronic address: mhammers@uoregon.edu.
⁸ Department of Chemistry & Biochemistry, 1253 University of Oregon, University of Oregon, Eugene, OR 97403, USA. Electronic address: pluth@uoregon.edu.
⁹ Matthew Mailing Centre for Translational Transplant Studies, 339 Windermere Rd., London Health Sciences Centre, London, Ontario N6A 5A5, Canada; Department of Microbiology and Immunology, Schulich Medicine and Dentistry, Dental Sciences Building Room 3014, Western University, London, Ontario N6A 5C1, Canada; Schulich School of Medicine and Dentistry, Clinical Skills Building, Western University, London, Ontario N6A 5C1, Canada. Electronic address: ilobb@uwo.ca.
¹⁰ Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Department of Oncology, Schulich Medicine and Dentistry, 790 Commissioners Rd. E Room A4901, London Regional Cancer Program, London, Ontario N6A 4L6, Canada. Electronic address: nicholas.power@lhsc.on.ca.
¹¹ London Regional Cancer Program, 790 Commissioners Rd. E, London Health Sciences Centre, London, Ontario N6A 5A5, Canada; Department of Oncology, Schulich Medicine and Dentistry, 790 Commissioners Rd. E Room A4901, London Regional Cancer Program, London, Ontario N6A 4L6, Canada. Electronic address: ann.chambers@lhsc.on.ca.
¹² Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Translational Prostate Cancer Research Laboratory, F3-124, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Department of Microbiology and Immunology, Schulich Medicine and Dentistry, Dental Sciences Building Room 3014, Western University, London, Ontario N6A 5C1, Canada. Electronic address: hon.leong@lhsc.on.ca.
¹³ Matthew Mailing Centre for Translational Transplant Studies, 339 Windermere Rd., London Health Sciences Centre, London, Ontario N6A 5A5, Canada; Department of Surgery, Schulich Medicine and Dentistry, 268 Grosvenor St., St Joseph's Hospital, London, Ontario N6A 4V2, Canada; Department of Microbiology and Immunology, Schulich Medicine and Dentistry, Dental Sciences Building Room 3014, Western University, London, Ontario N6A 5C1, Canada; Schulich School of Medicine and Dentistry, Clinical Skills Building, Western University, London, Ontario N6A 5C1, Canada; Multiorgan Transplant Program, 339 Windermere Rd., London Health Sciences Centre, London, Ontario N6A 5A5, Canada. Electronic address: alp.sener@lhsc.on.ca.

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel-Lindau (VHL)-deficiency, resulting in pseudohypoxic, angiogenic and glycolytic tumours. Hydrogen sulfide (H2S) is an endogenously-produced gasotransmitter that accumulates under hypoxia and has been shown to be pro-angiogenic and cytoprotective in cancer. It was hypothesized that H2S levels are elevated in VHL-deficient ccRCC, contributing to survival, metabolism and angiogenesis. Using the H2S-specific probe MeRhoAz, it was found that H2S levels were higher in VHL-deficient ccRCC cell lines compared to cells with wild-type VHL. Inhibition of H2S-producing enzymes could reduce the proliferation, metabolism and survival of ccRCC cell lines, as determined by live-cell imaging, XTT/ATP assay, and flow cytometry respectively. Using the chorioallantoic membrane angiogenesis model, it was found that systemic inhibition of endogenous H2S production was able to decrease vascularization of VHL-deficient ccRCC xenografts. Endogenous H2S production is an attractive new target in ccRCC due to its involvement in multiple aspects of disease.

Keywords: Angiogenesis; Cell hypoxia; Cell metabolism; Cell survival; Clear cell renal cell carcinoma; Hydrogen sulfide.

Publication types

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

MeSH terms

Animals
Carcinoma, Renal Cell / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Chick Embryo
Humans
Hydrogen Sulfide / antagonists & inhibitors*
Hydrogen Sulfide / metabolism*
Hydrogen Sulfide / pharmacology
Neovascularization, Pathologic / metabolism
Xenograft Model Antitumor Assays

Substances

Hydrogen Sulfide

Abstract

Publication types

MeSH terms

Substances

Grants and funding