title: Suppression of interactions between prostate tumor cell-surface integrin and endothelial ICAM-1 by simvastatin inhibits micrometastasis.
abstract: Cancer micrometastasis relies on the ability of cancer cells to secrete angiogenic modulators, to interact with the vascular endothelium, and to overcome the resistance offered by the endothelial-barrier. Being an essential step prior to metastasis, blockage of micrometastasis can have potential applications in cancer therapy and metastasis prevention. Due to poorly known molecular mechanisms leading to micrometastasis, developing therapeutic strategies to target prostate cancer utilizing drugs that block micrometastasis is far from reality. Here, we demonstrate the potential benefits of simvastatin in the inhibition of prostate cancer micrometastasis and reveal the novel molecular mechanisms underlying this process. First, we showed that simvastatin inhibited the ability of human PC3 prostate cancer cells for transendothelial migration in vitro. Second, our data indicated that simvastatin modulates the expression of tumor-derived factors such as angiopoietins and VEGF-A at the mRNA and protein levels by the PC3 cells, thus preventing endothelial-barrier disruption. Third, simvastatin directly activated endothelial cells and enhances endothelial-barrier resistance. Apart from this, our study revealed that simvastatin-mediated effect on PC3 micrometastasis was mediated through inhibition of integrin αv β3 activity and suppression of interaction between prostate cancer cell integrin αv β3 with endothelial ICAM-1.
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia, USA.
authors.forename: Belal
authors.initials: B
authors.lastname: Al-Husein
authors.forename: Anna
authors.initials: A
authors.lastname: Goc
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D061206:Neoplasm Micrometastasis / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D051176:beta Catenin / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D051176:beta Catenin; D018799:Intercellular Adhesion Molecule-1; D019821:Simvastatin
references.citation: Oncogene. 2007 Sep 13;26(42):6238-43
references.pmid: 17369840
references.citation: Vascul Pharmacol. 2007 Jan;46(1):1-9
references.pmid: 16920035
references.citation: Br J Pharmacol. 2009 Jul;157(6):962-73
references.pmid: 19438511
references.citation: Nat Med. 2000 Sep;6(9):1004-10
references.pmid: 10973320
references.citation: BMC Cancer. 2012 Sep 14;12:409
references.pmid: 22974127
references.citation: N Engl J Med. 2012 Nov 8;367(19):1792-802
references.pmid: 23134381
references.citation: Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1712-9
references.pmid: 11701455
references.citation: Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957-61
references.pmid: 6933445
references.citation: J Immunol. 2010 Oct 15;185(8):4846-55
references.pmid: 20861356
references.citation: Mol Med. 2000 Apr;6(4):251-67
references.pmid: 10949907
references.citation: J Immunol. 1986 Jul 1;137(1):245-54
references.pmid: 3086451
references.citation: PLoS One. 2012;7(10):e47994
references.pmid: 23133535
references.citation: J Cell Biochem. 2004 Mar 1;91(4):706-17
references.pmid: 14991762
references.citation: Am J Pathol. 1994 Jul;145(1):189-201
references.pmid: 7518194
references.citation: Annu Rev Pharmacol Toxicol. 2005;45:89-118
references.pmid: 15822172
references.citation: Med Res Rev. 2010 Jan;30(1):102-35
references.pmid: 19526461
references.citation: J Mol Med (Berl). 2009 May;87(5):507-14
references.pmid: 19219419
references.citation: J Pharmacol Exp Ther. 2011 Feb;336(2):496-505
references.pmid: 21059805
references.citation: Angiogenesis. 2008;11(3):277-88
references.pmid: 18415691
references.citation: Oncotarget. 2011 Dec;2(12):1176-90
references.pmid: 22202492
references.citation: Br J Cancer. 2012 May 8;106(10):1689-96
references.pmid: 22531631
references.citation: Physiol Rev. 2011 Jul;91(3):1071-121
references.pmid: 21742796
references.citation: Oncogene. 1999 Jul 15;18(28):4120-30
references.pmid: 10435593
references.citation: Am J Cardiol. 2005 Sep 5;96(5A):24F-33F
references.pmid: 16126020
references.citation: Cancer. 2010 Jul 15;116(14):3389-98
references.pmid: 20586112
references.citation: Int J Oncol. 2011 Jan;38(1):267-77
references.pmid: 21109949
references.citation: Br J Cancer. 2012 Aug 7;107(4):713-23
references.pmid: 22767145
references.citation: Cold Spring Harb Symp Quant Biol. 2002;67:267-73
references.pmid: 12858549
references.citation: Cancer Chemother Pharmacol. 2006 Jan;57(2):155-64
references.pmid: 16133537
references.citation: PLoS One. 2012;7(7):e40594
references.pmid: 22808202
references.citation: Nat Med. 2005 Nov;11(11):1188-96
references.pmid: 16227992
references.citation: Autoimmun Rev. 2003 Oct;2(6):332-8
references.pmid: 14550874
references.citation: Pharmacotherapy. 2012 Dec;32(12):1095-111
references.pmid: 23208836
references.citation: Eur J Cancer. 2011 Apr;47(6):819-30
references.pmid: 21354784
references.citation: Mol Oncol. 2012 Feb;6(1):62-72
references.pmid: 22153388