Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells

• Published in: Urologic oncology Vol. 35; no. 1; pp. 32.e9 - 32.e16
• Main Authors: Mang, Josef, M.D, Merkle, Konstanze, M.D, Heller, Martina, Schüler, Julia, D.V.M., Ph.D, Tolstov, Yanis, Ph.D, Li, Jielin, M.D, Hohenfellner, Markus, M.D, Duensing, Stefan, M.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2017
• Subjects: Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological Transport - drug effects; Cell Line, Tumor; Docetaxel; Down-Regulation; Drug Resistance, Neoplasm; ERK1/2; Humans; Male; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Protein Translocation Systems; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; raf Kinases - metabolism; Receptors, Androgen - metabolism; Taxoids - metabolism; Taxoids - pharmacology; Urology; Xenograft Model Antitumor Assays; Prostate cancer; ERK1/2; Docetaxel
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2016.07.017

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.