Constitutive and Inducible Expression of Invasionrelated Factors in PC-3 Prostate Cancer Cells

Abstract

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.

The role of AP-1 in self-sufficient proliferation and migration of cancer cells and its potential impact on an autocrine/paracrine loop

“…In addition to cytokines, extracellular enzymes such as matrix metalloproteinases (MMPs) which are secreted by cancer cells under control of AP-1 play a role in Fra-1 induction in the same cells through activation of EGFR [ 72 ]. Furthermore, lipids such as lysophosphatidic acid (LPA), were found to play an important role as autocrine factors to enhance the aggressiveness of TNBC [ 56 , 73 ], ovarian [ 74 – 76 ] and prostate [ 77 – 79 ] cancer under the control of AP-1. These findings along with the data presented in our study indicates a central role of AP-1 in operating these auto/paracrine loops to boost tumorigenesis and cancer progression (Figure 9 ).…”

Global Proteomics Analysis of Lysophosphatidic Acid Signaling in PC-3 Human Prostate Cancer Cells: Role of CCN1

“…For example, LPA induces TSP1 at the transcriptional level in rat cortical astrocytes through the LPA receptor LPAR1 [62]. LPA has been previously shown to induce TSP1 in PC-3 cells after an 8 h treatment [63]. Since both CCN1 and TSP1 bind to integrins, the net effect of simultaneously increasing both CCN1 and TSP1 is difficult to predict.…”