Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells

• Verfasst von: Mang, Josef [VerfasserIn]
• Verfasst von: Merkle, Konstanze [VerfasserIn]
• Verfasst von: Heller, Martina [VerfasserIn]
• Verfasst von: Tolstov, Yanis [VerfasserIn]
• Verfasst von: Li, Jielin [VerfasserIn]
• Verfasst von: Hohenfellner, Markus [VerfasserIn]
• Verfasst von: Duensing, Stefan [VerfasserIn]
• Titel: Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells
• Verf.angabe: Josef Mang, Konstanze Merkle, Martina Heller, Julia Schüler, Yanis Tolstov, Jielin Li, Markus Hohenfellner, Stefan Duensing
• Jahr: 2017
• Jahr des Originals: 2016
• Umfang: 8 S.
• Fussnoten: Available online 28 September 2016 ; Gesehen am 13.09.2018
• Titel Quelle: Enthalten in: Urologic oncology
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1995
• Jahr Quelle: 2017
• Band/Heft Quelle: 35(2017), 1, Seite 32.e9-32.e16
• ISSN Quelle: 1873-2496
• DOI: doi:10.1016/j.urolonc.2016.07.017
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Docetaxel
• Sach-SW: ERK1/2
• Sach-SW: Prostate cancer
• K10plus-PPN: 1580959954

Abstract

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.