α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway.
Existing anticancer strategies focused on disrupting integrin functions in tumor cells or tumor-involved endothelial cells have met limited success. An alternative strategy is to augment integrin-mediated pathways that suppress tumor progression, but how integrins can signal to restrain malignant behavior remains unclear. To address this issue, we generated an in vivo model of prostate cancer metastasis via depletion of α3β1 integrin, a correlation observed in a significant proportion of prostate cancers. Our data describe a mechanism whereby α3β1 signals through Abl family kinases to restrain Rho GTPase activity, support Hippo pathway suppressor functions, and restrain prostate cancer migration, invasion, and anchorage-independent growth. This α3β1-Abl kinase-Hippo suppressor pathway identified α3 integrin-deficient prostate cancers as potential candidates for Hippo-targeted therapies currently under development, suggesting new strategies for targeting metastatic prostate cancer based on integrin expression. Our data also revealed paradoxical tumor suppressor functions for Abl kinases in prostate cancer that may help to explain the failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials. Cancer Res; 76(22); 6577-87. ©2016 AACR.
Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Afshin
A
Varzavand
Department of Biochemistry, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Will
W
Hacker
Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Deqin
D
Ma
Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Katherine
K
Gibson-Corley
Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Maria
M
Hawayek
Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Omar J
OJ
Tayh
Department of Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
James A
JA
Brown
Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.|Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Michael D
MD
Henry
Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. christopher-stipp@uiowa.edu.|Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Christopher S
CS
Stipp
D000818:Animals; D049109:Cell Proliferation; D000090683:Hippo Signaling Pathway; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D039201:Integrin alpha3beta1; D017346:Protein Serine-Threonine Kinases
Oncogene. 2015 Feb 5;34(6):681-90
24531710
FASEB J. 2009 Dec;23(12):4231-43
19690215
Cell. 1990 Mar 9;60(5):849-59
2155708
Genes Dev. 2005 Sep 1;19(17):1974-9
16107613
J Cell Physiol. 2010 Aug;224(2):283-8
20432448
Nature. 2000 Aug 3;406(6795):532-5
10952316
Am J Transl Res. 2009 Apr 20;1(3):211-20
19956432
Invest New Drugs. 2012 Apr;30(2):749-57
21049281
Nat Rev Cancer. 2013 Aug;13(8):559-71
23842646
Cell. 2015 Nov 5;163(4):811-28
26544935
Cancer Cell. 2015 Jun 8;27(6):797-808
26058078
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21468-73
23236172
Cancer Res. 2010 Aug 1;70(15):6359-67
20631072
J Cell Sci. 2014 Mar 15;127(Pt 6):1179-89
24434582
J Neurosci. 2013 Apr 17;33(16):6742-52
23595732
Mol Cell Biol. 2015 Apr;35(8):1350-62
25645929
Oncogene. 2014 May 22;33(21):2779-89
23792450
Physiol Rev. 2014 Oct;94(4):1287-312
25287865
Invest New Drugs. 2011 Dec;29(6):1432-40
20336348
Neoplasia. 2002 May-Jun;4(3):243-54
11988844
J Cell Sci. 2009 Jul 1;122(Pt 13):2263-73
19509057
Mol Biol Cell. 2009 Apr;20(8):2207-17
19225155
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2441-50
22891335
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7411-5
7638207
Mol Cancer Res. 2014 Jan;12(1):143-54
24002891
Genes Dev. 2012 Jan 1;26(1):54-68
22215811
Nat Rev Drug Discov. 2014 Jan;13(1):63-79
24336504
Ann Oncol. 2013 Feb;24(2):329-36
23104724
Mol Biol Cell. 2011 Sep;22(17):3263-75
21757538
Oncogene. 2014 Aug 21;33(34):4286-95
24077284
Cell Commun Signal. 2013 Apr 24;11(1):31
23618389
J Natl Cancer Inst. 2003 Mar 19;95(6):458-70
12644539
EMBO J. 2011 May 18;30(10):1896-906
21487391
Clin Exp Metastasis. 2013 Apr;30(4):541-52
23224938
J Clin Invest. 2011 Aug;121(8):3176-88
21747168
Cancer Biol Ther. 2015;16(11):1626-40
26418968
Oncogene. 2012 Apr 5;31(14):1804-16
21892207
Nature. 2013 Jan 3;493(7430):106-10
23178811
Methods Enzymol. 2012;504:183-200
22264535
Chem Biol. 2011 Feb 25;18(2):177-86
21338916
Oncogene. 2013 May 23;32(21):2622-30
22777352
Cell Adhes Commun. 1996 Jul;4(1):41-52
8870972
Sci Signal. 2016 Feb 02;9(413):ra12
26838548
J Biol Chem. 2011 Mar 4;286(9):7496-506
21193415
J Cell Sci. 2004 Aug 1;117(Pt 17):3947-59
15265981
Cell Stem Cell. 2015 Oct 1;17(4):448-61
26321201
Nat Med. 2012 Oct;18(10):1511-7
23001183
Expert Opin Investig Drugs. 2013 Jun;22(6):787-94
23540855
Genes Dev. 2007 Nov 1;21(21):2747-61
17974916