Heterogeneity in plasminogen activator (PA) levels in human prostate cancer cell lines: Increased PA activity correlates with biologically aggressive behavior

Keer, Harold; Gaylis, Franklin; Kozlowski, James M.; Kwaan, Hau C.; Bauer, Kenneth D.; Sinha, Akhouri A.; Wilson, Michael J.

doi:10.1002/pros.2990180303

Cited by 55 publications

(36 citation statements)

References 18 publications

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“…In contrast, Laniado et al (57) showed a narrow range of variation between these two prostate cancer cell lines, whereas Dahiya et al (58) reported a higher invasive capacity for LNCaP cells. Keer et al (59) reported that PC-3 cells had a considerably higher invasive capacity compared with DU-145 cells in agreement with the present study. Explanations for these differences include, variations within cell lines and/or the loss of certain adhesion molecules over time and passage number and also differences in the expression of MMP activity as shown in the present study.…”

Section: Discussionsupporting

confidence: 93%

Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells

et al. 2004

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Section: Discussionsupporting

confidence: 93%

Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells

et al. 2004

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“…studies have shown that PC3 cells are highly metastatic, whereas DU145 and LNCaP cells are moderately and poorly metastatic, respectively (45)(46)(47)(48). Because uPA and its receptor uPAR are involved in tumor invasion and metastasis, we first compared the levels of these proteins in the three human prostate cancer cell lines with different metastatic potentials.…”

Section: Endogenous Upa and Upar Protein Expression Is Associated Witmentioning

confidence: 99%

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

Pulukuri

Gondi

Lakka

et al. 2005

Journal of Biological Chemistry

245

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The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator-(uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion and survival, and the potential of uPA and uPAR as targets for prostate cancer therapy. uPA and uPAR expression correlates with the metastatic potential of prostate cancer cells. Thus, therapies designed to inhibit uPA and uPAR expression would be beneficial. LNCaP, DU145, and PC3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as demonstrated by their capacity to invade the extracellular matrix. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPA and uPAR. These small interfering RNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Our data demonstrated that uPA-uPAR knockdown in PC3 cells resulted in a dramatic reduction of tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNA interference for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as ERK1/2 and Stat 3. In addition, our results demonstrated that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation, and survival of prostate cancer cells. Thus, RNA interference-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.

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“…4A). In PC3 cells, which have a high metastatic potential (20,27), pioglitazone treatment showed no significant effect on invasiveness of the cells compared to that of the control vehicle-treated cells (41.9% Ϯ 2.0% for control-treated cells versus 32.2% Ϯ 8.6% for pioglitazone-treated cells), whereas decreased invasion was observed when PC3 cells were treated with valproic acid (24.0% Ϯ 2.3%). Strikingly, a synergistic effect on the inhibition of invasion was observed when a combination of pioglitazone and valproic acid was used (11.4% Ϯ 3.1%).…”

Section: Synergistic Action Of Ppar␥ Agonists and Hdac Inhibitorsmentioning

confidence: 91%

Peroxisome Proliferator-Activated Receptor γ Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer

Annicotte

Iankova

Miard

et al. 2006

Molecular and Cellular Biology

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) might not be permissive to ligand activation in prostate cancer cells. Association of PPAR␥ with repressing factors or posttranslational modifications in PPAR␥ protein could explain the lack of effect of PPAR␥ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPAR␥ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPAR␥ agonists, defining a new class of PPAR␥ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.Prostate cancer is the most common form of cancer in men and the second leading cause of cancer deaths. Tumor growth is originally androgen dependent. Androgens exert their effects through activation of the androgen receptor (AR), a member of the hormone nuclear receptor superfamily. In the mature prostatic gland, the AR regulates the expression of genes involved in cell division and proliferation of the epithelial cells (26). The AR is also involved in several other aspects of prostate cellular metabolism, including lipid biosynthesis, and controls the production of specialized secretory proteins with prostate-restricted expression, such as prostate-specific antigen (PSA) (26). When prostate cancer is still hormone dependent, androgen ablation therapy causes regression of the tumor (18), likely through inactivation of the transcription of the AR target genes. However, the durability of this response is inadequate and many men develop recurrent androgen-independent prostate cancer, which has a very poor prognosis (see reference 11 for a review). Other nuclear receptors or locally produced factors that interact with nuclear receptors are likely involved in cell proliferation, differentiation, and apoptosis in the prostate. The peroxisome proliferator-activated receptor ␥ (PPAR␥) is one such factor. PPAR␥ is another member of the hormone nuclear receptor superfamily. As for most of the other members of this family, its activity is regulated by ligands. Prostaglandin J2 and the antidiabetic drugs thiazolidinediones have been determined to be natural and synthetic ligands of PPAR␥, respectively (for a review, see reference 9). PPAR␥ is highly expressed in the adipose tissue and is required for its development through regulation of the expression of adipocyte-specific genes, such as lipoprotein lipase or the fatty acid transport protein aP2. PPAR␥ is expressed in several other tissues in add...

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Heterogeneity in plasminogen activator (PA) levels in human prostate cancer cell lines: Increased PA activity correlates with biologically aggressive behavior

Cited by 55 publications

References 18 publications

Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells

Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

Peroxisome Proliferator-Activated Receptor γ Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer

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