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.
Highlights
Flavopiridol (FP) is a pan-cyclin dependent kinase inhibitor, which shows strong efficacy in inducing cancer cell apoptosis
Since it is known that massive apoptotic death produces fragments which negatively influence the survival of the remaining cells, the culture medium was changed with newly prepared medium daily
To further explore the mechanisms involved in the sensitivity of FP in prostate cancer cells, we investigated the effect of FP treatment in the DU145FP cells with suppressed mitochondrial function
Summary
Flavopiridol (FP) is a pan-cyclin dependent kinase inhibitor, which shows strong efficacy in inducing cancer cell apoptosis. 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. We treated the DU145 prostate cancer cells with 400 nM FP and discovered that after an initial induction of apoptosis in majority of the cells, less than 1% of the DU145 cells survived and underwent an adaptation process of about 46 days These cells slowly resumed proliferation and emerged as a FP-tolerant cell line (DU145FP line). The present study provides sufficient evidence that FP induced mitochondrial lesions can initiate cell metabolism remodeling and up-regulate cancer cell stemness, highlighting potential contributions of the mechanisms in FP treatment failure
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