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Sci Rep. 2017 Jul 11;7(1):5081. doi: 10.1038/s41598-017-05086-6.

Metabolic reprogramming is associated with flavopiridol resistance in prostate cancer DU145 cells.

Author information

1
Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway.
2
Department of Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway.
3
Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, China.
4
Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450001, China.
5
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China.
6
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway.
7
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.
8
Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, Oslo, 0372, Norway.
9
Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, 100191, China.
10
Department of Urology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway.
11
Departments of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway.
12
Department of Cell Therapy, Cancer Institute, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway.
13
Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway. zhenhes@medisin.uio.no.
14
Department of Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway. zhenhes@medisin.uio.no.

Abstract

Flavopiridol (FP) is a pan-cyclin dependent kinase inhibitor, which shows strong efficacy in inducing cancer cell apoptosis. Although FP is potent against most cancer cells in vitro, unfortunately it proved less efficacious in clinical trials in various aggressive cancers. To date, the molecular mechanisms of the FP resistance are mostly unknown. Here, we report that a small fraction human prostate cancer DU145 cells can survive long-term FP treatment and emerge as FP-resistant cells (DU145FP). These DU145FP cells show accumulated mitochondrial lesions with stronger glycolytic features, and they proliferate in slow-cycling and behave highly migratory with strong anti-apoptotic potential. In addition, the cells are less sensitive to cisplatin and docetaxel-induced apoptotic pressure, and over-express multiple stem cell associated biomarkers. Our studies collectively uncover for the first time that FP-resistant prostate cancer cells show metabolic remodeling, and the metabolic plasticity might be required for the FP resistance-associated cancer cell stemness up-regulation.

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