α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

Afshin Varzavand; Will Hacker; Deqin Ma; Katherine Gibson-Corley; Maria Hawayek; Omar J Tayh; James A Brown; Michael D Henry; Christopher S Stipp

doi:10.1158/0008-5472.CAN-16-1483

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α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

Journal article

Open access

Peer reviewed

α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

Afshin Varzavand, Will Hacker, Deqin Ma, Katherine Gibson-Corley, Maria Hawayek, Omar J Tayh, James A Brown, Michael D Henry and Christopher S Stipp

Cancer research (Chicago, Ill.), Vol.76(22), pp.6577-6587

11/15/2016

DOI: 10.1158/0008-5472.CAN-16-1483

PMCID: PMC5290210

PMID: 27680681

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Abstract

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.

Prostatic Neoplasms - metabolism

Prostatic Neoplasms - pathology

Cell Proliferation

Signal Transduction

Humans

Protein-Serine-Threonine Kinases - genetics

Male

Integrin alpha3beta1 - genetics

Neoplasm Metastasis

Animals

Prostatic Neoplasms - genetics

Mice

Protein-Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway
Creators: Afshin Varzavand - Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Will Hacker - Department of Biochemistry, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Deqin Ma - Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Katherine Gibson-Corley - Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Maria Hawayek - Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Omar J Tayh - Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
James A Brown - Department of Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Michael D Henry - Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Christopher S Stipp - Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.76(22), pp.6577-6587
DOI: 10.1158/0008-5472.CAN-16-1483
PMID: 27680681
PMCID: PMC5290210
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: P30 CA086862 / NCI NIH HHS R01 CA130916 / NCI NIH HHS R01 CA136664 / NCI NIH HHS
Language: English
Date published: 11/15/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Dermatology; Molecular Physiology and Biophysics; Pathology; Biology; Radiation Oncology; Biochemistry and Molecular Biology; Urology; Ophthalmology and Visual Sciences
Record Identifier: 9983992094602771

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