Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells

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• 作者：Josef Mang ; M.D.^a ; ¹ ; Konstanze Merkle ; M.D.^a ; ¹ ; Martina Heller^a ; ¹ ; Julia Schü ; ler ; D.V.M. ; Ph.D.^b ; ¹ ; Yanis Tolstov ; Ph.D.^a ; ¹ ; Jielin Li ; M.D.^a ; Markus Hohenfellner ; M.D.^c ; Stefan Duensing ; M.D.^a ; ^{stefan.duensing@med.uni-heidelberg.de}
• 关键词：Prostate cancer ; Docetaxel ; ERK1/2
• 刊名：Urologic Oncology: Seminars and Original Investigations
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：35
• 期：1
• 页码：32.e9-32.e16
• 全文大小：1543 K
• 卷排序：35

文摘

Taxanes are widely used for the treatment of men with metastatic, castration-resistant prostate cancer, but their mode of action is poorly understood. One hypothesis is that taxanes function by disrupting the microtubule-dependent transport of the androgen receptor (AR). We found that the nuclear translocation of the AR is undisturbed by docetaxel at clinically relevant concentrations. Instead, both docetaxel and cabazitaxel cause a significant down-regulation of the ERK1/2 survival signal. Although the extent of the down-regulation correlated with cytotoxicity, inhibition of ERK1/2 alone was clearly not sufficient to cause cytotoxicty in the range seen with taxanes. Hence, additional, yet to be eluciated, mechanisms are likely to be involved. Collectively, our results highlight that taxanes impinge on pathways other than AR translocation, which may explain the cooperative effects of taxanes and antiandrogens observed in the CHAARTED or STAMPEDE clinical trials.