Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells
| Autor: | Jielin Li, Konstanze Merkle, Martina Heller, Julia Schüler, Josef Mang, Yanis Tolstov, Markus Hohenfellner, Stefan Duensing |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Oncology medicine.medical_specialty MAP Kinase Signaling System Urology Down-Regulation Antineoplastic Agents Docetaxel Proto-Oncogene Proteins p21(ras) Androgen deprivation therapy 03 medical and health sciences Prostate cancer 0302 clinical medicine Cell Line Tumor Internal medicine medicine Animals Humans Mode of action Cytotoxicity Mitosis Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Taxane business.industry Prostatic Neoplasms Biological Transport medicine.disease Xenograft Model Antitumor Assays Androgen receptor 030104 developmental biology Drug Resistance Neoplasm Receptors Androgen 030220 oncology & carcinogenesis Protein Translocation Systems Cancer research Taxoids raf Kinases business medicine.drug |
| Zdroj: | Urologic Oncology: Seminars and Original Investigations. 35:32.e9-32.e16 |
| ISSN: | 1078-1439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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