GRK3 is essential for metastatic cells and promotes prostate tumor progression

The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen agains...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-01, Vol.111 (4), p.1521-1526
Main Authors: Li, Wenliang, Ai, Nanping, Wang, Suming, Bhattacharya, Nandita, Vrbanac, Vladimir, Collins, Michael, Signoretti, Sabina, Hu, Yanhui, Boyce, Frederick M., Gravdal, Karsten, Halvorsen, Ole J., Nalwoga, Hawa, Akslen, Lars A., Ed Harlow, Watnick, Randolph S.
Format: Article
Language:English
Subjects:
Angiogenesis
Biochemistry
Biological Sciences
Cancer
Cell growth
Cell lines
Cell Proliferation
Disease Progression
Endothelial cells
G-Protein-Coupled Receptor Kinase 3 - physiology
Humans
Kinases
Male
Metastasis
Neoplasm Metastasis
Plasminogen Activator Inhibitor 2 - genetics
Prostate
Prostate cancer
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Thrombospondin 1 - genetics
Tumor cell line
Tumors
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Summary:The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein–coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1320638111