title: Growth Arrest-Specific 6 (GAS6) Promotes Prostate Cancer Survival by G1Arrest/S Phase Delay and Inhibition of Apoptosis During Chemotherapy in Bone Marrow.
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 fraction of cells in G1and the duration of phase in PCa cells. Importantly, the effect of GAS6 on G1is potentiated during docetaxel chemotherapy. GAS6 altered the levels of several key cell cycle regulators, including the downregulation of Cyclin B1 (G2/M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry), while the upregulation of cell cycle inhibitors p27 and p21, Cyclin D1, and CDK4. Importantly, these changes became further accentuated during docetaxel treatment in the presence of GAS6. Moreover, GAS6 alters the apoptotic response of PCa cells during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis is efficiently suppressed in PCa cell culture 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. Docetaxel induced significant levels of Caspase-3 and PARP cleavage 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 will have important implications for targeting metastatic disease. J. Cell. Biochem. 117: 2815-2824, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Eunsohl
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.|Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, 48109, Michigan.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Cackowski
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Lulia A
authors.initials: LA
authors.lastname: Kana
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yumoto
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, 48109, Michigan.
authors.forename: Laura
authors.initials: L
authors.lastname: Buttitta
authors.affiliation: Department of Urology, University of Michigan School of Medicine, Ann Arbor, 48109, Michigan.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan. rtaich@umich.edu.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000077143:Docetaxel; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects*; D043823:Taxoids / Q000494:pharmacology; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000077143:Docetaxel; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043823:Taxoids; D000099255:Growth Arrest-Specific Protein 6
keywords: APOPTOTIC PATHWAY; BONE MARROW; DOCETAXEL; G1 ARREST/S PHASE DELAY; GAS6; PROSTATE CANCER