Src activation by β-adrenoreceptors is a key switch for tumor metastasis

Armaiz-Pena, Guillermo N.; Allen, Julie K.; Cruz, Anthony; Stone, Rebecca L.; Nick, Alpa M.; Lin, Yvonne G.; Han, Liz Y; Mangala, Lingegowda S; Villares, Gabriel J.; Vivas-Mejia, Pablo; Rodriguez-Aquayo, Cristian; Nagaraja, Archana S.; Gharpure, Kshipra M.; Wu, Zheng; English, Robert D.; Soman, Kizhake V.; Shazhad, Mian M. K.; Zigler, Maya; Deavers, Michael T.; Zien, Alexander; Soldatos, Theodoros G.; Jackson, David B; Wiktorowicz, John E.; Torres-Lugo, Madeline; Young, Tom; De Geest, Koen; Gallick, Gary E.; Bar-Eli, Menashe; Lopez-Berestein, Gabriel; Cole, Steve W.; López, Gustavo E.; Lutgendorf, Susan K.; Sood, Anil K.

doi:10.1038/ncomms2413

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Src activation by β-adrenoreceptors is a key switch for tumor metastasis

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Author(s): Guillermo N. Armaiz-Pena ¹ , Julie K. Allen ¹ ^, ¹⁰ , Anthony Cruz ⁷ , Rebecca L. Stone ¹ , Alpa M. Nick ¹ , Yvonne G. Lin ¹ , Liz Y. Han ¹ , Lingegowda S. Mangala ¹ ^, ⁶ , Gabriel J. Villares ² ^, ¹⁰ , Pablo Vivas-Mejia ³ ^, ¹⁶ , Cristian Rodriguez-Aquayo ³ , Archana S. Nagaraja ¹ ^, ¹⁰ , Kshipra M. Gharpure ¹ ^, ¹⁰ , Zheng Wu ¹¹ ^, ¹² , Robert D. English ¹¹ , Kizhake V. Soman ¹¹ ^, ¹² , Mian M. K. Shazhad ¹ , Maya Zigler ² ^, ¹⁰ , Michael T. Deavers ⁴ , Alexander Zien ⁹ , Theodoros G. Soldatos ⁹ , David B. Jackson ⁹ , John E. Wiktorowicz ¹¹ ^, ¹² , Madeline Torres-Lugo ⁸ , Tom Young ¹⁷ , Koen De Geest ¹³ , Gary E. Gallick ⁵ , Menashe Bar-Eli ² , Gabriel Lopez-Berestein ² ^, ³ ^, ⁶ , Steve W. Cole ¹⁴ , Gustavo E. Lopez ⁷ , Susan K. Lutgendorf ¹³ ^, ¹⁵ , Anil K. Sood ¹ ^, ² ^, ⁶

Publication date PMC-release: 29 July 2013

Journal: Nature communications

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Abstract

Norepinephrine (NE) can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here, we identify Src as a key regulator of phosphoproteomic signaling networks activated in response to beta-adrenergic signaling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth. In human ovarian cancer samples, high tumoral NE levels were correlated with high pSrc ^Y419 levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signaling in the tumor microenvironment.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101528555

Journal ID (pubmed-jr-id): 37539

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature communications

ISSN (Electronic): 2041-1723

Publication date Nihms-submitted: 28 December 2012

Publication date (Print): 29 January 2013

Publication date PMC-release: 29 July 2013

Volume: 4

Page: 1403

Affiliations

[1 ]Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[2 ]Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[3 ]Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[4 ]Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[5 ]Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[6 ]Center for RNA Interference and Non-coding RNA, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

[7 ]Department of Chemistry, University of Puerto Rico, Mayaguez, Puerto Rico 00681, USA

[8 ]Department of Chemical Engineering, University of Puerto Rico, Mayaguez, Puerto Rico 00681, USA

[9 ]Molecular Health GmbH, Belfortstr. 2, 69115 Heidelberg, Germany

[10 ]Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas 77030, USA

[11 ]Biomolecular Resource Facility, The University of Texas Medical Branch, Galveston, Texas 77555, USA

[12 ]Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA

[13 ]Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa 52242, USA

[14 ]Department of Medical Oncology Hematology, University of California, Los Angeles, California 90095, USA

[15 ]Department of Psychology, Urology, and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA

[16 ]Department of Biochemistry and Cancer Center, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico 00935, USA

[17 ]Department of Chemistry, Lehman College, Bronx, New York 10468, USA

Author notes

[* ]Correspondence and requests for materials should be addressed to A.K.S. ( asood@ 123456mdanderson.org )

Article

Manuscript ID: NIHMS430501

DOI: 10.1038/ncomms2413

PMC ID: 3561638

PubMed ID: 23360994

SO-VID: 75d52517-7722-4fea-a4e4-95ebc2f47a0e

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