title: Atorvastatin inhibited Rho-associated kinase 1 (ROCK1) and focal adhesion kinase (FAK) mediated adhesion and differentiation of CD133+CD44+ prostate cancer stem cells.
abstract: Prostate cancer has become a global health concern and is one of the leading causes of cancer death of men after lung and gastric cancers. It has been suggested that the 3-hydroxy-3-methyl-glutarylcoenzyme-CoA (HMG-CoA) reductase inhibitor atorvastatin shows anticancer activity in prostate cancer cell lines. To this end, we analyzed the influence of atorvastatin on the cell adhesion and differentiation of CD133(+)CD44(+) cells derived from prostate cancer biopsies and peripheral blood. CD133(+)CD44(+) cells were treated with atorvastatin (16-64μM) for different time periods. Cell adhesion to endothelial cell monolayers and differentiation into prostate cancer cells were evaluated. α1, β1 and α2β1 integrins adhesion receptors and the downstream target of atorvastatin Rho-dependent kinase (ROCK) and focal adhesion kinase (FAK) were analyzed by Western blot. Further blocking studies with the ROCK inhibitor H1152, anti-FAK antibody and anti-integrin α1 and β1 antibodies were carried out. Atorvastatin treatment inhibited dose-dependently cell attachment to endothelium and differentiation. The inhibitory effect of atorvastatin on cell adhesion was associated with decreased expression of integrins α1 and β1 and phosphorylated MYPT1 and FAK. Furthermore, atorvastatin strongly reduced ROCK1 and FAK mediated differentiation of CD133(+)CD44(+) cells, which was confirmed by antibody treatment. Atorvastatin modified the expression of cell adhesion molecules and differentiation markers. These beneficial effects of atorvastatin may be mediated by ROCK and FAK signaling pathway. The data presented may point to novel treatment options for prostate cancer.
authors.affiliation: Department of Biotechnology, GITAM University, Visakhapatnam, Andhra Pradesh, India. Electronic address: dr.rsn79@gmail.com.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rentala
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Chintala
authors.forename: Manohar
authors.initials: M
authors.lastname: Guda
authors.forename: Madhuri
authors.initials: M
authors.lastname: Chintala
authors.forename: Aruna Lakshmi
authors.initials: AL
authors.lastname: Komarraju
authors.forename: Lakshmi Narasu
authors.initials: LN
authors.lastname: Mangamoori
mesh_terms: D000071916:AC133 Antigen; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D006023:Glycoproteins / Q000032:analysis; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010455:Peptides / Q000032:analysis; D011467:Prostate / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D006023:Glycoproteins; D006538:Heptanoic Acids; D018960:Hyaluronan Receptors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000606023:PROM1 protein, human; D010455:Peptides; D011758:Pyrroles; D000069059:Atorvastatin; D051417:Focal Adhesion Kinase 1; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases
keywords: Differentiation and signaling cascade; FAK; Integrin; Prostate cancer stem cell; ROCK1