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Stable Knock-Out Ovarian Cancer Cells Do Not Show Increased Sensitivity to Cisplatin and PARP Inhibitor Treatment. | LitMetric

Stable Knock-Out Ovarian Cancer Cells Do Not Show Increased Sensitivity to Cisplatin and PARP Inhibitor Treatment.

Front Oncol

Laboratory of Experimental Oncology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri Istituito di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

Published: July 2022

AI Article Synopsis

  • Cyclin-dependent kinase 12 (CDK12) plays a crucial role in regulating RNA polymerase II and is frequently mutated in ovarian cancer, impacting treatment response.
  • Researchers used CRISPR/Cas9 technology to create a CDK12 knockout in A2780 ovarian carcinoma cells, discovering that these knockout cells grew slower and had higher levels of apoptosis compared to normal cells.
  • Although the knockout cells showed changes in DNA repair gene expression and chromosomal abnormalities, there was no significant difference in their sensitivity to treatments like cisplatin and olaparib compared to normal cells.

Article Abstract

Cyclin-dependent kinase 12 (CDK12) is a serine/threonine kinase involved in the regulation of RNA polymerase II and in the transcription of a subset of genes involved in the DNA damage response. is one of the most mutated genes in ovarian carcinoma. These mutations result in loss-of-function and can predict the responses to PARP1/2 inhibitor and platinum. To investigate the role of CDK12 in ovarian cancer, CRISPR/Cas9 technology was used to generate a stable knockout (KO) clone in A2780 ovarian carcinoma cells. This is the first report on a null cell line. The clone had slower cell growth and was less clonogenic than parental cells. These data were confirmed , where KO transplanted cells had a much longer time lag and slightly slower growth rate than CDK12-expressing cells. The slower growth was associated with a higher basal level of apoptosis, but there were no differences in the basal level of autophagy and senescence. While cell cycle distribution was similar in parental and knockout cells, there was a doubling in DNA content, with an almost double modal number of chromosomes in the KO clone which, however did not display any increase in γH2AX, a marker of DNA damage. We found partial down-regulation of the expression of DNA repair genes at the mRNA level and, among the down-regulated genes, an enrichment in the G2/M checkpoint genes. Although the biological features of KO cells are compatible with the function of CDK12, contrary to some reports, we could not find any difference in the sensitivity to cisplatin and olaparib between wild-type and KO cells.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328802PMC
http://dx.doi.org/10.3389/fonc.2022.903536DOI Listing

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