title: Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines.
abstract: Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the integrin family of receptors. Our group previously discovered that the α6 integrin (ITGA6/CD49f) is post translationally modified by urokinase plasminogen activator (uPA) and its receptor, urokinase plasminogen activator receptor (uPAR), to form the variant ITGA6p. This variant of ITGA6 is a cleaved form of the receptor that lacks the ligand-binding domain. Although it is established that the uPA/uPAR axis drives ITGA6 cleavage, the mechanisms regulating cleavage have not been defined. Intracellular integrin dependent "inside-out" signaling is a major regulator of integrin function and the uPA/uPAR axis. We hypothesized that intracellular signaling molecules play a role in formation of ITGA6p to promote cell migration during cancer metastasis. In order to test our hypothesis, DU145 and PC3B1 prostate cancer and MDA-MB-231 breast cancer cell lines were treated with small interfering RNA targeting actin and the intracellular signaling regulators focal adhesion kinase (FAK), integrin linked kinase (ILK), and paxillin. The results demonstrated that inhibition of actin, FAK, and ILK expression resulted in significantly increased uPAR expression and ITGA6p production. Inhibition of actin increased ITGA6p, although inhibition of paxillin did not affect ITGA6p formation. Taken together, these results suggest that FAK and ILK dependent "inside-out" signaling, and actin dynamics regulate extracellular production of ITGA6p and the aggressive phenotype.
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Cancer Biology Interdisciplinary Graduate Program, University of Arizona, Tucson, AZ, United States.
authors.forename: Apollo D
authors.initials: AD
authors.lastname: Kacsinta
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Cancer Biology Interdisciplinary Graduate Program, University of Arizona, Tucson, AZ, United States.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Rubenstein
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Cancer Biology Interdisciplinary Graduate Program, University of Arizona, Tucson, AZ, United States.
authors.forename: Isis C
authors.initials: IC
authors.lastname: Sroka
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Pharmacology, University of Arizona, Tucson, AZ, United States.
authors.forename: Sangita
authors.initials: S
authors.lastname: Pawar
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Gard
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Pathology, University of Arizona, Tucson, AZ, United States.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States. Electronic address: acress@azcc.arizona.edu.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cress
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D039503:Integrin alpha6 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics; D015854:Up-Regulation; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039503:Integrin alpha6; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D000099200:Scaffold Protein ILK; C588002:ITGA6 protein, human
keywords: Actin; Cancer; Focal adhesion kinase; ITGA6; Integrin linked kinase; uPAR