title: Cyp24a1Attenuation Limits Progression ofBrafV600E-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600EInhibitor PLX4720.
abstract: CYP24A1, the primary inactivating enzyme for vitamin D, is often overexpressed in human cancers, potentially neutralizing the antitumor effects of calcitriol, the active form of vitamin D. However, it is unclear whether CYP24A1 expression serves as a functional contributor versus only a biomarker for tumor progression. In this study, we investigated the role of CYP24A1 on malignant progression of a murine model ofBrafV600E-induced papillary thyroid cancer (PTC). Mice harboring wild-typeCyp24a1(BVECyp24a1-wt) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion ofCyp24a1(BVECyp24a1-null) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVECyp24a1-null-derived tumor cells to be nearly abolished in immunocompromised nude mice. This phenotype was associated with downregulation of the MAPK, PI3K/Akt, and TGFβ signaling pathways and a loss of epithelial-mesenchymal transition (EMT) in BVECyp24a1-nullcells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVECyp24a1-nullcells, it strengthened antitumor responses to the BRAFV600Einhibitor PLX4720 in both BVECyp24a1-nulland BVECyp24a1-wtcells. Our findings offer direct evidence thatCyp24a1functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment.Cancer Res; 77(8); 2161-72. ©2017 AACR.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Minjing
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Essa Y
authors.initials: EY
authors.lastname: Baitei
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Huda A
authors.initials: HA
authors.lastname: BinEssa
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Parhar
authors.affiliation: Department of Surgery and Human Genetics, McGill University, Montreal, Quebec, Canada; and Research Centre, Shriners Hospitals for Children, Montreal, Quebec, Canada.
authors.forename: René
authors.initials: R
authors.lastname: St-Arnaud
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Biochemistry, University of Leicester, Lancaster Road, Leicester, UK.
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Alzahrani
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Assiri
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. yufei@kfshrc.edu.sa.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D002291:Carcinoma, Papillary; D018450:Disease Progression; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf