Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells

• Published in: International journal of oncology Vol. 48; no. 6; pp. 2330 - 2338
• Main Authors: OGURA, TAKEHARU, TANAKA, YOSHIYUKI, TAMAKI, HIROKI, HARADA, MAMORU
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.06.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Androgens; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bcl-2; Cancer therapies; caspase; Caspases - biosynthesis; Cell Line, Tumor; Cytochrome; cytotoxicity; Docetaxel; Drug Screening Assays, Antitumor; Drug therapy; Drugs; Experiments; Flow cytometry; Gene expression; Genetic aspects; Health aspects; Humans; Male; Mice; Mice, Inbred C3H; Mice, Nude; Patient outcomes; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Taxoids - pharmacology; Transfection; Tumor necrosis factor-TNF; Tumor suppressor genes; Xenograft Model Antitumor Assays; United States > US; Japan
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3482

Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemo-resistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases.