CYP11A1 Upregulation Leads to Trophoblast Oxidative Stress and Fetal Neurodevelopmental Toxicity That can be Rescued by Vitamin D

Wang, Xiang; Li, Mengxue; Zhang, Xueguang; Li, Yaqian; He, Guolin; Dinnyés, András; Qun, Sun; Xu, Wei

doi:10.3389/fmolb.2020.608447

Cited by 6 publications

(5 citation statements)

References 53 publications

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“…However, the molecular mechanisms underlying the anticancer effects of CYP11A1 on RCC are largely unknown. CYP11A1 reportedly triggers excessive oxidative stress in mitochondria against a human placental cell line derived from choriocarcinoma [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CYP11A1 recovers cell cycle distribution in renal cell carcinoma Caki-1

et al. 2022

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Background Clear cell renal carcinoma is commonly known for its metastasis propensity to outspread to other organs and is asymptomatic in the early stage. Recent studies have shown that deficiencies in CYP11A1 expression can lead to fatal adrenal failure if left untreated and are associated with downstream regulation in various cancer types. However, the molecular mechanisms of CYP11A1 and kidney cancer proliferation remain unclear. Methods Normal and renal carcinoma cell lines (HEK293 and Caki-1) were transfected with plasmid encoding CYP11A1 to overexpress the P450scc protein. Cell cycle distribution was investigated using flow cytometry. The expression of proteins related to C-Raf/ERK/JNK/p38 signaling pathways was examined using western blot. Results We observed that CYP11A1 overexpression suppressed the cyclin B1 and cell-division cycle 2 expression while cyclin-dependent kinases 2 and 4 were unaffected. Cancer cell migration and invasion were suppressed along with epithelial-intermediate metastatic markers Snail and Vimentin. In addition, in CYP11A1-overexpressing Caki-1 cells, cdc2/cyclinB1 was downregulated while the phosphorylation of cdc25c, a G2/M arrest-related upstream signal, was increased. The intrinsic-mitochondrial apoptosis markers were not significantly altered. We also identified that the C-Raf/ERK/JNK/p38 pathway is an important pro-apoptotic mechanism in CYP11A1-overexpressing cell-based models. Our results suggest that CYP11A1 overexpression recovered the disturbed cell cycle arrest distribution in renal carcinoma cell line Caki-1 through G2/M arrest and C-Raf/ERK/JNK pathway. Conclusions Our findings may suggest promising new therapeutic targets to suppress kidney cancer proliferation without affecting normal cells, eventually improving the survival of patients with cancer.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CYP11A1 recovers cell cycle distribution in renal cell carcinoma Caki-1

et al. 2022

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“…Overexpression of CYP11A1 increases ROS levels, as previously shown in our studies [ 14 ]. Moreover, excessive biosynthesis of CYP11A1 in mitochondria also leads to lipid peroxidation in BeWo cells [ 20 ]. In cellular membranes, lipid peroxidation is mainly responsible for ferroptosis, an iron-dependent cell death process [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Screening of Natural Compounds for CYP11A1 Stimulation Against Cell Renal Cell Carcinoma

Ong,

Ates,

Kwon

et al. 2023

Biol Proced Online

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Background Renal cancer therapies are challenging owing to the extensive spreading of this cancer to other organs and its ability to pose resistance to current medications. Therefore, drugs targeting novel targets are urgently required to overcome these challenges. The cholesterol side-chain cleavage enzyme (CYP11A1) is closely associated with steroidogenesis, and its downregulation is linked to adrenal dysfunction and several types of carcinoma. We previously found that overexpression of CYP11A1 inhibited epithelial-mesenchymal transition and induced G2/M arrest in the kidney cancer Caki-1 cell line. In this context, natural compounds that exhibit potent CYP11A1 stimulation activity can be promising therpaeutic agents for kidney cancer. Methods We screened a panel of 1374 natural compounds in a wound-healing assay using CYP11A1-transfected Caki-1 cells. Of these, 167 promising biologically active compounds that inhibited cancer cell migration by more than 75% were selected, and their half-maximal inhibitory concentrations (IC50) were determined. The IC50 of 159 compounds was determined and 38 compounds with IC50 values less than 50 µM were selected for further analysis. Steroid hormones (cholesterol and pregnenolone) levels in cells treated with the selected compounds were quantitated using LC–MS/MS to determine their effect on CYP11A1 activity. Western blotting for CYP11A1, autophagy signaling proteins, and ferroptosis regulators were performed to ivestigate the mechanisms underlying the action of the selected compounds. Results We screened five promising natural lead compounds that inhibited cancer cell proliferation after three screening steps. The IC50 of these compounds was determined to be between 5.9 and 14.6 μM. These candidate compounds increased the expression of CYP11A1 and suppressed cholesterol levels while increasing pregnenolone levels, which is consistent with the activation of CYP11A1. Our results showed that CYP11A1 activation inhibited the migration of cancer cells, promoted ferroptosis, and triggered autophagy signaling. Conclusions This study indicates that the CYP11A1-overexpressing Caki-1 cell line is useful for screening drugs against kidney cancer. The two selected compounds could be utilized as lead compounds for anticancer drug discovery, and specifically for the development of antirenal cancer medication.

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“…The upregulated CYP11A1 in placentas might suggest over‐oxygen consumption and oxidative stress. In the BeWo cell line, upregulation of CYP11A1 induced excessive mitochondrial oxidative stress 45 . In addition, CYP11A1 inhibited cell proliferation and induced apoptosis in extravillous trophoblast cells 46 .…”

Section: Discussionmentioning

confidence: 98%

“…In the BeWo cell line, upregulation of CYP11A1 induced excessive mitochondrial oxidative stress. 45 In addition, CYP11A1 inhibited cell proliferation and induced apoptosis in extravillous trophoblast cells. 46 However, another study of cadmium exposure-induced FGR identified that CYP11A1 expression and progesterone synthesis were reduced in the mice models as well as in human placentas of small for gestational age.…”

Section: Genesmentioning

confidence: 99%

Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction

Shi,

Zhou,

Cai

et al. 2023

The FASEB Journal

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Fetal growth restriction (FGR) is associated with increased susceptibility to perinatal morbidity and mortality. Evidence suggests that epigenetic changes play critical roles in the regulation of fetal growth. We sought to present a comprehensive analysis of the associations between placental DNA methylation and selective fetal growth restriction (sFGR), which is a severe complication of monochorionic twin pregnancies, characterized by one fetus experiencing restricted growth. Genome‐wide methylation analysis was performed on 24 placental samples obtained from 12 monochorionic twins with sFGR (Cohort 1) using Illumina Infinium MethylationEPIC BeadChip. Integrative analysis of our EPIC data and two previous placental methylation studies of sFGR (a total of 30 placental samples from 15 sFGR twins) was used to identify convincing differential promoter methylation. Validation analysis was performed on the placentas from 15 sFGR twins (30 placental samples), 15 FGR singletons, and 14 control singletons (Cohort 2) using pyrosequencing, quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry (IHC). A globe shift toward hypomethylation was identified in the placentas of growth‐restricted fetuses compared with the placentas of normal fetuses in monochorionic twins, including 5625 hypomethylated CpGs and 452 hypermethylated CpGs, especially in the regions of CpG islands, gene‐body and promoters. The analysis of pathways revealed dysregulation primarily in steroid hormone biosynthesis, metabolism, cell adhesion, signaling transduction, and immune response. Integrative analysis revealed a differentially methylated promoter region in the CYP11A1 gene, encoding a rate‐limiting enzyme of steroidogenesis converting cholesterol to pregnenolone. The CYP11A1 gene was validated to have hypomethylation and higher mRNA expression in sFGR twins and FGR singletons. In conclusion, our findings suggested that the changes in placental DNA methylation pattern in sFGR may have functional implications for differentially methylated genes and regulatory regions. The study provides reliable evidence for identifying abnormally methylated CYP11A1 gene in the placenta of sFGR.

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CYP11A1 Upregulation Leads to Trophoblast Oxidative Stress and Fetal Neurodevelopmental Toxicity That can be Rescued by Vitamin D

Cited by 6 publications

References 53 publications

Overexpression of CYP11A1 recovers cell cycle distribution in renal cell carcinoma Caki-1

Overexpression of CYP11A1 recovers cell cycle distribution in renal cell carcinoma Caki-1

Screening of Natural Compounds for CYP11A1 Stimulation Against Cell Renal Cell Carcinoma

Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction

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