title: Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.
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.
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Sonke
authors.affiliation: 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.
authors.forename: Megan
authors.initials: M
authors.lastname: Verrydt
authors.affiliation: London Regional Cancer Program, 790 Commissioners Rd. E, London Health Sciences Centre, London, Ontario N6A 5A5, Canada. Electronic address: cpostenk@uwo.ca.
authors.forename: Carl O
authors.initials: CO
authors.lastname: Postenka
authors.affiliation: 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.
authors.forename: Siddika
authors.initials: S
authors.lastname: Pardhan
authors.affiliation: 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.
authors.forename: Chantalle J
authors.initials: CJ
authors.lastname: Willie
authors.affiliation: 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.
authors.forename: Clarisse R
authors.initials: CR
authors.lastname: Mazzola
authors.affiliation: Department of Chemistry & Biochemistry, 1253 University of Oregon, University of Oregon, Eugene, OR 97403, USA. Electronic address: mhammers@uoregon.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hammers
authors.affiliation: Department of Chemistry & Biochemistry, 1253 University of Oregon, University of Oregon, Eugene, OR 97403, USA. Electronic address: pluth@uoregon.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pluth
authors.affiliation: 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.
authors.forename: Ian
authors.initials: I
authors.lastname: Lobb
authors.affiliation: 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.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Power
authors.affiliation: 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.
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.affiliation: 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.
authors.forename: Hon S
authors.initials: HS
authors.lastname: Leong
authors.affiliation: 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.
authors.forename: Alp
authors.initials: A
authors.lastname: Sener
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D006801:Humans; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D006862:Hydrogen Sulfide
keywords: Angiogenesis; Cell hypoxia; Cell metabolism; Cell survival; Clear cell renal cell carcinoma; Hydrogen sulfide