title: Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity.
abstract: Colony stimulating factor-1 (CSF-1) stimulates mononuclear phagocytic cell survival, growth and differentiation into macrophages through activation and autophosphorylation of the CSF-1 receptor (CSF-1R). We have previously demonstrated that CSF-1-induced phosphorylation of Y721 (pY721) in the receptor kinase insert triggers its association with the p85 regulatory subunit of phosphoinositide 3'-kinase (PI3K). Binding of p85 PI3K to the CSF-1R pY721 motif activates the associated p110 PI3K catalytic subunit and stimulates spreading and motility in macrophages and enhancement of tumor cell invasion. Here we show that pY721-based signaling is necessary for CSF-1-stimulated PtdIns(3,4,5)P production. While primary bone marrow-derived macrophages and the immortalized bone marrow-derived macrophage cell line M-/-.WT express all three class IA PI3K isoforms, p110δ predominates in the cell line. Treatment with p110δ-specific inhibitors demonstrates that the hematopoietically enriched isoform, p110δ, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110δ inhibitor, may have therapeutic potential by targeting the infiltrative capacity of tumor-associated macrophages that is critical for their enhancement of tumor invasion and metastasis.
authors: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Kellie A
authors: KA
authors: Mouchemore
authors: Natalia G
authors: NG
authors: Sampaio
authors: Michael W
authors: MW
authors: Murrey
authors: E Richard
authors: ER
authors: Stanley
authors: Brian J
authors: BJ
authors: Lannutti
authors: Fiona J
authors: FJ
authors: Pixley
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D016186:Receptor, Macrophage Colony-Stimulating Factor; C060974:phosphatidylinositol 3,4,5-triphosphate; C421683:Pik3cd protein, mouse; C552946:idelalisib
keywords: CSF-1R; GS-1101; PI3K p110δ; invasion: macrophage
references: Blood. 2011 Sep 29;118(13):3603-12
references: 21803855
references: Cancer Res. 2007 Jun 1;67(11):5064-6
references: 17545580
references: Cancer Res. 2008 Feb 15;68(4):1100-9
references: 18281485
references: Br J Cancer. 1994 Feb;69(2):342-6
references: 8297732
references: Mol Reprod Dev. 1997 Jan;46(1):71-4
references: 8981366
references: J Cell Sci. 2008 Dec 15;121(Pt 24):4124-33
references: 19033389
references: Cancer Res. 2005 Jun 15;65(12):5278-83
references: 15958574
references: Nat Rev Immunol. 2009 Apr;9(4):259-70
references: 19282852
references: Blood. 2011 Jan 13;117(2):591-4
references: 20959606
references: Trends Cell Biol. 2004 Nov;14(11):628-38
references: 15519852
references: J Immunol. 1988 Jul 15;141(2):575-9
references: 3290341
references: J Cell Sci. 2005 May 1;118(Pt 9):1873-83
references: 15860730
references: J Exp Med. 2001 Mar 19;193(6):727-40
references: 11257139
references: J Biol Chem. 2007 Jun 29;282(26):18991-9
references: 17420256
references: J Natl Cancer Inst. 1994 Jan 19;86(2):120-6
references: 8271294
references: Biochem Soc Trans. 2007 Apr;35(Pt 2):242-4
references: 17371249
references: J Cell Sci. 2011 Jul 1;124(Pt 13):2120-31
references: 21670198
references: Biochim Biophys Acta. 2009 Aug;1796(1):11-8
references: 19269310
references: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references: 20379207
references: Blood. 2010 Sep 2;116(9):1460-8
references: 20505158
references: J Pathol. 2002 Mar;196(3):254-65
references: 11857487
references: Cancer Res. 2006 Jan 1;66(1):192-7
references: 16397232
references: Crit Rev Clin Lab Sci. 2012 Mar-Apr;49(2):49-61
references: 22468857
references: J Biol Chem. 1977 Jun 25;252(12):4305-12
references: 301140
references: J Leukoc Biol. 2008 Sep;84(3):852-63
references: 18519746
references: Int J Cell Biol. 2012;2012:501962
references: 22505929
references: Nat Cell Biol. 1999 May;1(1):69-71
references: 10559867
references: J Cell Sci. 2011 Jun 15;124(Pt 12):2021-31
references: 21610095
references: Cancer Res. 2004 Aug 1;64(15):5378-84
references: 15289345
references: Cancer Res. 2004 Oct 1;64(19):7022-9
references: 15466195
references: Nat Rev Immunol. 2008 Jul;8(7):533-44
references: 18551128
references: Eur Cytokine Netw. 2002 Jan-Mar;13(1):121-7
references: 11956031
references: Curr Opin Oncol. 2012 Nov;24(6):643-9
references: 22960555
references: Blood. 2012 Feb 23;119(8):1897-900
references: 22210877
references: Blood. 2012 Oct 25;120(17):3501-9
references: 22955911