Cyp24a1 Attenuation Limits Progression of BrafV600E-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 -induced papillary thyroid cancer (PTC). Mice harboring wild-type (BVE) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of (BVE) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVE-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 cells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVE cells, it strengthened antitumor responses to the BRAF inhibitor PLX4720 in both BVE and BVE cells. Our findings offer direct evidence that functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment. .

RETRACTED ARTICLE: Downregulation of NEAT1 reverses the radioactive iodine resistance of papillary thyroid carcinoma cell via miR-101-3p/FN1/PI3K-AKT signaling pathway

“…LncRNA NEAT1 was first considered to be associated with SC35 splicing domains [16]. It has been revealed to function in multiple cancers through a variety of mechanisms, such as sponging miRNAs, enhancing EMT and stimulating apoptosis or autophagy [17,18]. Recently, Liu et al reported that NEAT1 promoted metastasis in ovarian cancer by miR-382-3p/ROCK1 axis.…”

“…Furthermore, our bioinformatics analysis predicted PI3K/AKT signaling pathway was dysregulated in RAI-resistant PTC. PI3K/AKT signaling pathway involved a lot in drug resistance, such as cisplatin-resistance in non-small cell lung cancer [1] and ovarian cancer [23], dacarbazine in melanoma cells [24] as well as PLX4720 in PTC [17], etc. In our study, we determined the differential expression of PI3K, AKT and ERK, as well as the corresponding phosphorylated protein.…”

The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity

“…Our study in KRAS mutant lung AC was based on our previous work as well as by others that suggested that KRAS mutant lung AC was associated with higher CYP24A1 expression (22,35). Others have recently reported that RAF signaling can be attenuated by inhibiting CYP24A1 (36,37) and in an independent study B-RAF was reported to be a CDH1 substrate interacting via its D-box (D#4) to regulate B-RAF abundance (38). To our surprise, we noted that a combination treatment of MEKi and simvastatin promotes CYP24A1 proteasomal degradation to reduce clonogenic survival of mutant KRAS-driven lung cancer cells (Fig.…”

Knockdown of CYP24A1 Aggravates 1α,25(OH)2D3-Inhibited Migration and Invasion of Mouse Ovarian Epithelial Cells by Suppressing EMT

“…We found that the expression of CYP24A1 in M-I cells was dramatically higher than that in M-L cells following 1α,25(OH) 2 D 3 treatment. Previous research has also revealed aberrantly high levels of CYP24A1 in multiple kinds of cancer cells, including ovarian cancer, breast cancer, thyroid cancer, and glioma cells (38)(39)(40)(41), thereby making them resistant to 1α,25(OH) 2 D 3 . Loss of CYP24A1 therefore facilitated the antitumor efficacy of 1α,25(OH) 2 D 3 in lung (42), colorectal (19), endometrial (43) and thyroid cancer cells (17).…”