title: Insulin-like growth factor 1 stimulation of androgen receptor activity requires β(1A)  integrins.
abstract: Despite the findings that β1 integrins play a vital role in the regulation of cell proliferation and survival, the mechanisms through which they operate and lead to cancer progression remain elusive. Previously, our laboratory has shown that β(1A) integrins support insulin-like growth factor 1 (IGFI)-mediated mitogenic and transforming activities. Here, we report that β(1A) integrins regulate basal levels of IGF-IR, although they are not critical for maintaining cancer cell morphology. Upon transfection of β(1A) siRNA and consequent downregulation of IGF-IR, we show inhibition of anchorage-independent growth of prostate cancer cells, a function which is dependent on IGF-IR expression. In addition, we demonstrate that IGFI-mediated activation of androgen receptor (AR), known to occur in prostate cancer cells, requires expression of β(1A) integrins as evaluated by luciferase reporter assays and immunoblotting analysis. Since β(1A) integrin levels are increased by R1881 or dihydrotestosterone (DHT), our results imply that β(1A) integrins support an androgen-enhanced feedback loop that regulates the expression of IGF-IR. β(1A) integrins also regulate inducible levels of IGF-IR in cells stimulated by androgen or by a combination of androgen and IGFI, as evaluated by flow cytometric analysis and immunoblotting. Furthermore, upon transfection of β(1A) siRNA and consequent downregulation of IGF-IR, neither activation of AKT, an effector of IGF-IR, nor AR levels are affected. We conclude that β(1A) integrin expression is critical for maintaining the regulatory crosstalk between IGF-IR and AR.
authors.affiliation: Department of Cancer Biology, Prostate Cancer Discovery and Development Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Sayeed
authors.forename: Naved
authors.initials: N
authors.lastname: Alam
authors.forename: Marco
authors.initials: M
authors.lastname: Trerotola
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000728:Androgens; D000818:Animals; D045744:Cell Line, Tumor; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000728:Androgens; D019012:Integrin beta1; D011944:Receptors, Androgen; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1