Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer

• Published in: PloS one 2014-02, Vol.9 (2), p.e89940
• Main Authors: Chanda, Diptiman, Lee, Joo Hyoung, Sawant, Anandi, Hensel, Jonathan A, Isayeva, Tatyana, Reilly, Stephanie D, Siegal, Gene P, Smith, Claire, Grizzle, William, Singh, Raj, Ponnazhagan, Selvarangan
• Format: Article
• Language: English
• Subjects: Adhesion; Androgens; Animals; Apoptosis; Biology; Bone cancer; Bone lesions; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Breast cancer; Cancer; Cancer metastasis; Caspase; Caspase-3; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Adhesion - genetics; Cell Death - drug effects; Cell Death - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Cluster Analysis; Collagen; Collagen (type I); Collagen (type IV); Conditioning; Development and progression; Fibrinogen; Fibronectin; Fibronectins; Gene Expression; Gene Expression Profiling; Gene Silencing; Genomics; Humans; Immunoglobulins; Integrins; Integrins - genetics; Integrins - metabolism; Laboratories; Laminin; Lesions; Male; Medicine; Metastases; Metastasis; Mice; Mucoproteins; Neoplasm Metastasis; Oncogene Proteins; Pathology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Proteins - genetics; Proteins - metabolism; Resistance factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signaling; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089940

Anterior Gradient Protein (AGR-2) is reported to be over-expressed in many epithelial cancers and promotes metastasis. A clear-cut mechanism for its observed function(s) has not been previously identified. We found significant upregulation of AGR-2 expression in a bone metastatic prostate cancer cell line, PC3, following culturing in bone marrow-conditioned medium. Substantial AGR-2 expression was also confirmed in prostate cancer tissue specimens in patients with bone lesions. By developing stable clones of PC3 cells with varying levels of AGR-2 expression, we identified that abrogation of AGR-2 significantly reduced cellular attachment to fibronectin, collagen I, collagen IV, laminin I and fibrinogen. Loss of cellular adhesion was associated with sharp decrease in the expression of α4, α5, αV, β3 and β4 integrins. Failure to undergo apoptosis following detachment is a hallmark of epithelial cancer metastasis. The AGR-2-silenced PC3 cells showed higher resistance to Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) induced apoptosis in vitro. This observation was also supported by significantly reduced Caspase-3 expression in AGR-2-silenced PC3 cells, which is a key effector of both extrinsic and intrinsic death signaling pathways. These data suggest that AGR-2 influence prostate cancer metastasis by regulation of cellular adhesion and apoptosis.