Publication Date:
2016-05-06
Description:
ABSTRACT Prostate cancer (PCa) is known to develop resistance to chemotherapy. Growth arrest-specific 6 (GAS6), plays a role in tumor progression by regulating growth in many cancers. Here, we explored how GAS6 regulates the cell cycle and apoptosis of PCa cells in response to chemotherapy. We found that GAS6 is sufficient to significantly increase the number and duration of G 1 phase in PCa cells. Importantly, GAS6 further increased the number of G 1 arrested cells during docetaxel chemotherapy. GAS6 altered the signals of key cell cycle regulators: Cyclin B1 (G 2 /M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry) were all downregulated, while p27, p21, Cyclin D1, and CDK4 (G 0 /G 1 phase) were upregulated. Importantly, these signaling events were further accentuated during docetaxel treatment in the presence of GAS6. Moreover, the apoptotic response of PCa cells to GAS6 was examined during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis. However, this apoptotic response was abrogated in PCa cell cultures in the presence of GAS6 or GAS6 secreted from co-cultured osteoblasts. Similarly, the GAS6-expressing bone environment protects PCa cells from apoptosis within primary tumors in vivo studies. In addition, docetaxel induced significant levels of Caspase-3 and PARP cleavages in PCa cells, while GAS6 protected PCa cells from docetaxel-induced apoptotic signaling. Together, these data suggest that GAS6, expressed by osteoblasts in the bone marrow, plays a significant role in the regulation of PCa cell survival during chemotherapy, which may have important implications for targeting metastatic disease. This article is protected by copyright. All rights reserved
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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