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

• Published in: Scientific reports 2017-07, Vol.7 (1), p.5081-20, Article 5081
• Main Authors: Li, Xiaoran, Lu, Jie, Kan, Quancheng, Li, Xiaoli, Fan, Qiong, Li, Yaqing, Huang, Ruixia, Slipicevic, Ana, Dong, Hiep Phuc, Eide, Lars, Wang, Junbai, Zhang, Hongquan, Berge, Viktor, Goscinski, Mariusz Adam, Kvalheim, Gunnar, Nesland, Jahn M., Suo, Zhenhe
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/31; 14; 14/34; 14/63; 38; 38/91; 631/67/2327; 631/67/71; 9/10; Apoptosis; Apoptosis - drug effects; Biomarkers, Tumor - metabolism; Cell Division - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cisplatin; Cisplatin - pharmacology; Clinical trials; Docetaxel - pharmacology; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Flavonoids - pharmacology; Flavonoids - therapeutic use; Flavopiridol; G2 Phase - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; Humanities and Social Sciences; Humans; Male; Membrane Potential, Mitochondrial - drug effects; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular modelling; multidisciplinary; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Piperidines - pharmacology; Piperidines - therapeutic use; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Pseudopodia - drug effects; Pseudopodia - metabolism; Science; Science (multidisciplinary); Stem cells; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05086-6

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 (DU145 FP ). These DU145 FP 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.