title: IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.
abstract: Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR) mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa) cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.
authors.affiliation: Department of Cancer Biology, Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Sayeed
authors.forename: Carmine
authors.initials: C
authors.lastname: Fedele
authors.forename: Marco
authors.initials: M
authors.lastname: Trerotola
authors.forename: Kirat K
authors.initials: KK
authors.lastname: Ganguly
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D039081:Integrin alpha5beta1; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D046988:Proteasome Endopeptidase Complex