title: Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer.
abstract: The receptor tyrosine kinase Axl is overexpressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our laboratory indicate that Axl and its ligand growth arrest-specific 6 (GAS6) may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer cell lines PC3 and DU145 and has negligible levels of expression in a nonmetastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial-mesenchymal transition in prostate cancer cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were downregulated. Moreover, CoCl(2), a hypoxia mimicking agent, prevented GAS6-mediated downregulation of Axl in these cell lines. Immunochemical staining of human prostate cancer tissue microarrays showed that Axl, GAS6, and hypoxia-inducible factor-1α (Hif-1α; indicator of hypoxia) were all coexpressed in prostate cancer and in bone metastases compared with normal tissues. Together, our studies indicate that Axl plays a crucial role in prostate cancer metastasis and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression is maintained leading to enhanced signaling.
authors.affiliation: Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, MI 48109, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.forename: Samantha
authors.initials: S
authors.lastname: McGee
authors.forename: Jinkoo
authors.initials: J
authors.lastname: Kim
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.forename: Jeena
authors.initials: J
authors.lastname: Joseph
authors.forename: Janice E
authors.initials: JE
authors.lastname: Berry
authors.forename: Aaron
authors.initials: A
authors.lastname: Havens
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D016587:Antimutagenic Agents / Q000494:pharmacology; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D016587:Antimutagenic Agents; D015820:Cadherins; D003035:Cobalt; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C018021:cobaltous chloride; C000722289:AXL protein, human