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Hwang, Young Sun,Lee, Jongsung,Zhang, Xianglan,Lindholm, Paul F. Springer-Verlag 2016 TUMOR BIOLOGY Vol.37 No.5
<P>We have demonstrated previously that increased RhoA and nuclear factor (NF)-kappa B activities are associated with increased PC-3 prostate cancer cell invasion and that lysophosphatidic acid (LPA) significantly increases cancer invasion through RhoA and NF-kappa B activation. In this study, we identified the intermediate signaling molecules and specialized cell structures which are activated by LPA, resulting in enhanced cellular invasion. LPA-induced Akt and I kappa B alpha signaling pathways were necessary for RhoA and NF-kappa B activation, and these LPA effects were abolished by RhoA inhibition. Mice injected with PC-3 cells expressing dominant negative RhoA N19 developed significantly less tumor growth compared with those injected with control (pcDNA 3.1). In addition, LPA treatment increased functional invadopodia formation. Activation of RhoA and NF -kappa B through the Akt and I kappa B alpha signaling pathway was required for LPA-stimulated gelatin degradation activity. LPA administration increased tumor growth and osteolytic lesions in a mouse xenograft model. These results indicate that LPA promotes PC-3 cell invasion by increasing functional invadopodia formation via upregulating RhoA and NF-kappa B signaling which contributes to prostate cancer progression. Therefore, the LPA and RhoA-NF-kappa B signaling axis may represent key molecular targets to inhibit prostate cancer invasion and progression.</P>
Constitutive and Inducible Expression of Invasionrelated Factors in PC-3 Prostate Cancer Cells
황영선,Paul F. Lindholm 대한암예방학회 2015 Journal of cancer prevention Vol.20 No.2
Background:Tumor growth and invasion are interconnected with the tumor microenvironment. Overexpression of genes that regulate cancer cell invasion by growth factors, cytokines, and lipid factors can affect cancer aggressiveness. A comparative gene expression analysis between highly invasive and low invasive cells revealed that various genes are differentially expressed in association with invasive potential. In this study, we selected variant PC-3 prostate cancer cell sublines and discovered critical molecules that contributed to their invasive potential. Methods: The high invasive and low invasive variant PC-3 cell sublines were obtained by serial selection following Matrigel-coated Transwell invasion and were characterized by Transwell invasion, luciferase reporter assay, and Rhotekin pull-down assay. Lysophosphatidic acid (LPA) was added to the cultures to observe the response to this extracellular stimulus. The essential molecules related with cancer invasiveness were detected with Northern blotting, quantitative reverse transcription-polymerase chain reaction, and cDNA microarray. Results:Highly invasive PC-3 cells showed higher nuclear factor kappa B (NF-κB), activator protein 1 (AP-1) and RhoA activities than of low invasive PC-3 cells. LPA promoted cancer invasion through NF-κB, AP-1, and RhoA activities. Thrombospondin-1, interleukin-8, kallikrein 6, matrix metalloproteinase-1, and tissue factor were overexpressed in the highly invasive PC-3 variant cells and further upregulated by LPA stimulation. Conclusions:The results suggest that the target molecules are involved in invasiveness of prostate cancer. These molecules may have clinical value for anti-invasion therapy by serving as biomarkers for the prediction of aggressive cancers and the detection of pharmacological inhibitors.