Breast Cancer Migration and Invasion Depend on Proteasome Degradation of Regulator of G-Protein Signaling 4

Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Cancer Research (Impact Factor: 9.33). 07/2009; 69(14):5743-51. DOI: 10.1158/0008-5472.CAN-08-3564
Source: PubMed


Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through G(i)-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple G(i)-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.

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Available from: Taotao Wei, Jul 11, 2014
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    • "Breast cancer is the leading cause of cancer deaths of women , and metastatic breast cancer is invariably incurable . Metastasis begins with the migration and invasion of cancer cells into surrounding tissues and lymphatics , and then to target organs . We previously described some of the intracellular regulators of breast cancer cell metastasis ( Xie et al . , 2009 ; Zhao et al . , 2013a ) , particularly as they relate to the formation of the lamellipodia . The driving force for lamellipodia formation is localized polymerization of F - actin filaments beneath the plasma membrane , which requires an abundance of ATP ; accordingly , inhibition of energy metabolism by ESeroS - GS abolishes cancer cel"
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    • "Matrigel invasion assays were performed at 37 C using 24-well Transwell inserts coated with 30 mg of Matrigel [26] [27]. After incubation with 40 or 80 mg/ml PEG-GO for 24 h, cells (50,000) were suspended in 200 ml of serum-free medium and added to the upper chamber, and the migration inducer (NIH-3T3 cell-conditioned medium) was added to the lower chamber. "
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    • "een those results and our current data could be due to cell type - specific effects . Also , RGS2 mRNA and protein levels are likely to be differentially regulated as we previously showed that RGS2 protein is rapidly degraded by the ubiquitin - proteasomal pathway . This was certainly true in the case of RGS4 in a study by the group of Yaping Tu ( Xie et al . , 2009 ) . They found that RGS4 mRNA levels in metastatic breast cancer cells were . 20 , 000 higher than in control cells . At the protein level , however , RGS4 was virtually undetectable , whereas the nonmetastatic cells demonstrated robust RGS4 protein expression ."
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