Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells
Background: Taxanes are routinely used to treat men with advanced prostate cancer, yet their molecular mode of action is poorly characterized. Taxanes stabilize microtubules and may hence interfere with a plethora of cellular processes, most notably mitosis. However, prostate cancer is typically a s...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2017
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| In: |
Urologic oncology
Year: 2016, Volume: 35, Issue: 1, Pages: 32.e9-32.e16 |
| ISSN: | 1873-2496 |
| DOI: | 10.1016/j.urolonc.2016.07.017 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.urolonc.2016.07.017 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1078143916302034 
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| Author Notes: | Josef Mang, Konstanze Merkle, Martina Heller, Julia Schüler, Yanis Tolstov, Jielin Li, Markus Hohenfellner, Stefan Duensing |
| Summary: | Background: Taxanes are routinely used to treat men with advanced prostate cancer, yet their molecular mode of action is poorly characterized. Taxanes stabilize microtubules and may hence interfere with a plethora of cellular processes, most notably mitosis. However, prostate cancer is typically a slowly growing tumor suggesting that additional processes play a role in the response to taxanes. Methods: Here, we analyzed the potential effect of taxanes on microtubuli-dependent intracellular transport and signaling processes, specifically, nuclear translocation of the androgen receptor and modulation of the RAS-RAF-MEK-ERK signaling cascade. Results: We show that the androgen-driven nuclear translocation of the androgen receptor remains virtually undisturbed by docetaxel in prostate cancer cells. However, we found a striking down-regulation of activated ERK1/2 together with enhanced cytotoxicity in both docetaxel or cabazitaxel-treated cells that was comparable to direct MEK kinase inhibition. Remarkably, MEK inhibition alone was less effective in inducing cytotoxicity than taxanes indicating that a down-regulation of activated ERK1/2 may be necessary but is not sufficient for taxane-induced antitumoral effects. In line with this notion, we show in a xenograft mouse model that prostate cancer cells that are resistant to docetaxel overexpress activated ERK1/2. Taken together, our findings underscore that the modulation of ERK1/2 activation, in concert with other mechanisms, plays an important role in taxane-induced antineoplastic effects on prostate cancer cells. Conclusions: These results suggest at least partially nonoverlapping effects of docetaxel and androgen deprivation therapy and hence help to understand recent clinical findings. A further elucidation of the mode of action of docetaxel would have important implications to optimize current treatment strategies and biomarker development for men with metastatic prostate cancer. |
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| Item Description: | Available online 28 September 2016 Gesehen am 13.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1873-2496 |
| DOI: | 10.1016/j.urolonc.2016.07.017 |