RNAseq reveals extensive metabolic disruptions in the sensitive SF-295 cell line treated with schweinfurthins.

Autor: Weissenrieder JS; Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA.; Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.; Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Mail Code CH72, Hershey, PA, 17033-0850, USA., Weissenkampen JD; Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA., Reed JL; Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.; Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Mail Code CH72, Hershey, PA, 17033-0850, USA., Green MV; Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.; Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Mail Code CH72, Hershey, PA, 17033-0850, USA., Zheng C; Department of Pharmacology, The University of Iowa, Iowa City, IA, USA., Neighbors JD; Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.; Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Mail Code CH72, Hershey, PA, 17033-0850, USA., Liu DJ; Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA., Hohl RJ; Department of Medicine, Penn State College of Medicine, Hershey, PA, USA. rhohl@pennstatehealth.psu.edu.; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA. rhohl@pennstatehealth.psu.edu.; Penn State Cancer Institute, Penn State College of Medicine, 500 University Drive, Mail Code CH72, Hershey, PA, 17033-0850, USA. rhohl@pennstatehealth.psu.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Jan 10; Vol. 12 (1), pp. 359. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41598-021-04117-7
Abstrakt: The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. In some cell lines, such as SF-295 glioma cells, schweinfurthins elicit cytotoxicity at nanomolar concentrations. However, other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations. At this time, the precise mechanism of action and target for these compounds is unknown. Here, we employ RNA sequencing of cells treated with 50 nM schweinfurthin analog TTI-3066 for 6 and 24 h to elucidate potential mechanisms and pathways which may contribute to schweinfurthin sensitivity and resistance. The data was analyzed via an interaction model to observe differential behaviors between sensitive SF-295 and resistant A549 cell lines. We show that metabolic and stress-response pathways were differentially regulated in the sensitive SF-295 cell line as compared with the resistant A549 cell line. In contrast, A549 cell had significant alterations in response genes involved in translation and protein metabolism. Overall, there was a significant interaction effect for translational proteins, RNA metabolism, protein metabolism, and metabolic genes. Members of the Hedgehog pathway were differentially regulated in the resistant A549 cell line at both early and late time points, suggesting a potential mechanism of resistance. Indeed, when cotreated with the Smoothened inhibitor cyclopamine, A549 cells became more sensitive to schweinfurthin treatment. This study therefore identifies a key interplay with the Hedgehog pathway that modulates sensitivity to the schweinfurthin class of compounds.
(© 2022. The Author(s).)
Databáze: MEDLINE
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