<i>Cyp24a1</i> Attenuation Limits Progression of <i>BrafV600E</i> -Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor 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 of <i>Braf^V600E</i> -induced papillary thyroid cancer (PTC). Mice harboring wild-type <i>Cyp24a1</i> (BVE^Cyp24a1-wt) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of <i>Cyp24a1</i> (BVE^Cyp24a1-null) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVE^Cyp24a1-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 BVE^Cyp24a1-null cells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVE^Cyp24a1-null cells, it strengthened antitumor responses to the BRAF^V600E inhibitor PLX4720 in both BVE^Cyp24a1-null and BVE^Cyp24a1-wt cells. Our findings offer direct evidence that <i>Cyp24a1</i> functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment. <i>Cancer Res; 77(8); 2161-72. ©2017 AACR</i>.