PAF1-mediated transcriptional reprogramming confers docetaxel resistance in advanced prostate cancer.

Autor: Muniyan S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: s.muniyan@unmc.edu., Vengoji R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Nimmakayala RK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Seshacharyulu P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Perumalsamy B; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Alsafwani ZW; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Kakar SS; Department of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USA., Smith LM; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Shonka N; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Internal Medicine, Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Teply BA; Department of Internal Medicine, Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Lele SM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: sbatra@unmc.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2025 Jan 28; Vol. 609, pp. 217355. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1016/j.canlet.2024.217355
Abstrakt: Advanced prostate cancer (PCa) remains a significant clinical challenge, and docetaxel plays a significant role in disease management. Despite the efficacy of docetaxel as a first-line chemotherapy, resistance often develops. We developed three clinically relevant in vitro PCa cell models and transcriptomic analysis identified that the Paf1/RNA polymerase II complex component (PAF1)-associated pluripotent-transcription factor (TF), SOX2, plays a crucial role in docetaxel resistance. The cancer stem cell (CSC) transcriptional master regulator PAF1 is significantly higher in PCa cell lines, tumor tissues, and docetaxel resistant (DR) PCa cells than in age-matched control cells. To determine the molecular underlying and functional characteristics of PAF1 in resistance mechanisms, we performed coimmunoprecipitation, embryonic stem cell network proteins, in vitro tumor-initiating ability, and 3D multicellular organoid growth using PAF1 knockdown cells. Tet-inducible PAF1 depletion reduced the drug-efflux phenotype, tumor-initiating frequencies, and three-dimensional organoid growth of the docetaxel-resistant PCa cell lines. Functional studies also showed restoration of docetaxel sensitivity in a 3D tumorsphere model upon PAF1 depletion. PAF1 depletion was also associated with decreased pluripotent TFs and other CSC markers. This study provides a novel regulatory mechanism of docetaxel resistance in PCa through PAF1.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is a founding member of Sanguine Diagnostics and Therapeutics, Inc. Other authors have nothing to disclose.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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