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An unprecedented endocrine target for ovarian cancer: inhibiting 17β-HSD7 supresses cancer cell proliferation and arrests G2/M cycle.

ABSTRACT: Epithelial ovarian cancer, widely suggested as endocrine-related cancer, yields a low survival rate among patients. Despite intensive research for nearly a century, there have been no fundamental advances in treatment. The reductive 17β-HSD7 is a special enzyme possessing a remarkable dual activity in both the biosynthesis of the most potent estrogen estradiol and the inactivation of the most active androgen dihydrotestosterone. In the present study, we observed over-expression of 17β-HSD7 in EOC cells such as OVCAR-3 and SKOV-3, in agreement with integrative data analysis demonstrating overexpression of 17β-HSD7 in EOC tissues. After knocking down 17β-HSD7, SKOV-3 cell proliferation decreased by 29%, cell arrest in the G2/M phase increased by 25% with cyclin B1/Cdk1 inhibition. Inhibition of 17β-HSD7 in EOC cells triggered negative feedback of its expression, which further decreased the estradiol level to more than 60% under the experimental condition. Such inhibition increased the dihydrotestosterone level to many times higher and suppressed cell proliferation. Thus, 17β-HSD7 is demonstrated to be a promising target for the endeavor against the malignant ovarian cancer, a menace in human life. The targeting of such an enzyme thus provides exceptional scientific importance.

SUBMITTER: Wang R

PROVIDER: S-EPMC8640825 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe disordered cell cycle and dysregulated expression of numerous oncogenes involved in tumor-relevant processes are highly related to the tumorigenesis of cervical cancer. Cyclin-dependent kinase 7 (CDK7) constitutes the indispensable catalytic subunit of CDK-activating kinase (CAK), which is required for both cell cycle transition and transcriptional regulation. However, research regarding the antitumor effects of CDK7 inhibition in cervical cancer remains unclear.PurposeOur study aims to explore the antineoplastic effects of the CDK7 inhibitor THZ1 in cervical cancer cells and to find a potential agent for cervical cancer treatment.MethodsThe CRISPR-Cas9 system was used to knock down CDK7. The Cell Counting Kit-8 (CCK-8) assay was used to detect the cell viability after CDK7 depletion and THZ1 treatment. Western blot was employed to detect protein expression. The expression levels of mRNA were assayed through qRT-PCR. Flow cytometry analysis was used to assay the apoptotic cells and cell cycle distribution. Gene expression microarray analysis was used to identify the differential expression of the genes. Subcutaneous xenograft mouse model was performed to test the antineoplastic effects of THZ1 in vivo.ResultsWe revealed that the genetic depletion of CDK7 using the CRISPR-Cas9 system exhibited great cell growth inhibition in cervical cancer cell lines, consistent with the effects of CDK7 blocking using THZ1. Cervical cancer cells were highly sensitive to THZ1 treatment, and a low concentration of THZ1 could induce substantial cell apoptosis. THZ1 specifically perturbed the phosphorylation of cell cycle regulator CDK1 and decreased the expression of cyclin B1, leading to a cell cycle blockage at the G2/M phase and inducing cell growth inhibition. The gene expression microarray analysis showed that massive oncogene transcripts, especially those associated with tumorigenesis, were preferential suppressed after THZ1 treatment. The qRT-PCR confirmed that several essential oncogenes in tumorigenesis (c-MYC, hTERT, RAD51, and BCL-2) and HPV viral oncogenes (E6 and E7) were preferentially repressed by THZ1. Moreover, THZ1 exhibited substantial antineoplastic effects against cervical cancer in vivo without inducing obvious side effects.ConclusionThese findings indicated that the CDK7 inhibitor THZ1 is a potential option in cervical cancer treatment owing to its ability to inhibit cell cycle progression and transcriptional activity.

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An unprecedented endocrine target for ovarian cancer: inhibiting 17β-HSD7 supresses cancer cell proliferation and arrests G2/M cycle.

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