title: The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination.
abstract: Aberrant cholesterol homeostasis and biosynthesis has been observed in different tumour types. This paper investigates the role of the post-squalenic enzyme of cholesterol biosynthesis, oxidosqualene cyclase (OSC), in regulating tumour angiogenesis and metastasis dissemination in mouse models of cancer. We showed that Ro 48-8071, a selective inhibitor of OSC, reduced vascular density and increased pericyte coverage, with a consequent inhibition of tumour growth in a spontaneous mouse model of pancreatic tumour (RIP-Tag2) and two metastatic mouse models of human colon carcinoma (HCT116) and pancreatic adenocarcinoma (HPAF-II). Remarkably, the inhibition of OSC hampered metastasis formation in HCT116 and HPAF-II models. Ro 48-8071 induced tumour vessel normalization and enhanced the anti-tumoral and anti-metastatic effects of 5-fluorouracil (5-FU) in HCT116 mice. Ro 48-8071 exerted a strong anti-angiogenic activity by impairing endothelial cell adhesion and migration, and by blocking vessel formation in angiogenesis assays. OSC inhibition specifically interfered with the PI3K pathway. According to in vitro results, Ro 48-8071 specifically inhibited Akt phosphorylation in both cancer cells and tumour vasculature in all treated models. Thus, our results unveil a crucial role of OSC in the regulation of cancer progression and tumour angiogenesis, and indicate Ro 48-8071 as a potential novel anti-angiogenic and anti-metastatic drug.
authors.affiliation: 1] Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95. 10060, Candiolo, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.affiliation: 1] Laboratory of Biochemistry and Molecular Biology, University of Turin, Via P. Giuria 9, 10125, Turin, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Oliaro-Bosso
authors.affiliation: 1] Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95. 10060, Candiolo, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Meda
authors.affiliation: 1] Laboratory of Cancer Epigenetics, Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95. 10060, Candiolo, Italy [2] Department of Oncology, University of Turin, 10100, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: 1] Laboratory of Vascular Oncology, Candiolo Cancer Institute, IRCCS, Str prov 142 Km 3.95. 10060, Candiolo, Italy [2] Department of Oncology, University of Turin, 10100, Turin, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.affiliation: 1] Laboratory of Biochemistry and Molecular Biology, University of Turin, Via P. Giuria 9, 10125, Turin, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
authors.affiliation: 1] Laboratory of Biochemistry and Molecular Biology, University of Turin, Via P. Giuria 9, 10125, Turin, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Viola
authors.affiliation: 1] Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95. 10060, Candiolo, Italy [2] Department of Science and Drug Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001577:Benzophenones; C105726:Ro 48-8071; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D005472:Fluorouracil