Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis

Chen, Shang Chiung; Henry, Dale O.; Reczek, Peter R.; Wong, Michael K.

doi:10.1158/1535-7163.mct-08-0051

Cited by 31 publications

(25 citation statements)

References 28 publications

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“…Previous studies have shown that cell adhesion is associated with vulnerability to apoptosis (28, 29). Here, we confirmed that the suppression of PAI-1 resulted in a significant dose–response reduction in cellular adhesion in parental T24, UM-UC-14, and UROtsa cells after pretreatment with tiplaxtinin for 30 minutes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model

Gomes-Giacoia

Miyake

Goodison

et al. 2013

Molecular Cancer Therapeutics

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Cancers of the urinary bladder result in aggressive and highly angiogenic tumors for which standard treatments have only limited success. Patients with advanced disease have a 5-year survival rate of less than 20%, and no new anticancer agent has been successfully introduced into the clinic armamentarium for the treatment of bladder cancer in more than 20 years. Investigations have identified plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, as being highly expressed in several malignancies, including bladder cancer, in which high expression is associated with a poor prognosis. In this study, we evaluated PAI-1 as a potential therapeutic target for bladder cancer. PAI-1 expression was manipulated in a panel of cell lines and functional inhibition was achieved using the small molecule tiplaxtinin. Reduction or inhibition of PAI-1 resulted in the reduction of cellular proliferation, cell adhesion, and colony formation, and the induction of apoptosis and anoikis in vitro. Treatment of T24 xenografts with tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in tumor growth. Similar results were obtained through evaluation of the human cervical cancer HeLa cell line, showing that PAI-1–mediated effects are not restricted to tumor cells of bladder origin. Collectively, these data show that targeting PAI-1 may be beneficial and support the notion that novel drugs such as tiplaxtinin could be investigated as anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model

Gomes-Giacoia

Miyake

Goodison

et al. 2013

Molecular Cancer Therapeutics

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“…Whether PAI-1 protects (myo)fibroblasts from apoptosis in old mouse lung through inhibiting plasmin activity, caspase-3 activity, or p53 expression remains to be determined. We also want to point out that although PAI-1 protects fibroblasts from apoptosis (Chang and others 2010; Horowitz and others 2008; Huang and others 2012; Zhang and others 2013), opposite effects have been observed in other types of cells (Abderrahmani and others 2012; Bajou and others 2008; Bhandary and others 2013; Chen and others 2008; Shetty and others 2012). Whether PAI-1 expression is increased with age in other types of cells in the lung and how PAI-1 regulates apoptosis sensitivity in these other types of cells is unknown and is under active investigation in this lab.…”

Section: Discussionmentioning

confidence: 98%

Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis

Huang

Akhter

Jiang

et al. 2015

Experimental Gerontology

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Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.

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“…These findings convincingly indicated that PAI-1 played an important role in the pathogenesis of BLM-induced lung fibrosis and that inhibition of PAI-1 expression with siRNA might be a potential therapeutic target for treatment of lung PAI-1 regulates a variety of cellular processes, including adhesion, migration, detachment, angiogenesis, proliferation and apoptosis, in vitro and in vivo [19,20] . PAI-1 is a paradoxical protein that exerts different effects in various cell lines [21][22][23][24] . Previous studies have shown that PAI-1 could protect fibrosarcoma cells from etoposide-induced apoptosis [25] and augment the proliferation of vascular smooth muscle cells [26] .…”

Section: Discussionmentioning

confidence: 99%

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

Zhang

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: Plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. The present study was undertaken to examine the effects on pulmonary fibrosis of silencing PAI-1 expression with small interfering RNA (siRNA) and to assess the possible underlying mechanisms. Methods: Male Wistar rats were subjected to intratracheal injection of bleomycin (BLM, 5 mg/kg, 0.2 mL) to induce pulmonary fibrosis. Histopathological changes of lung tissue were examined with HE or Masson's trichrome staining. The expression levels of α-smooth muscle actin (α-SMA), collagen type-I and type-III, caspase-3, as well as p-ERK1/2 and PI3K/Akt in the lung tissue were evaluated using immunohistochemistry and Western blot analysis. The fibroblasts isolated from BLM-induced fibrotic lung tissue were cultured and transfected with pcDNA-PAI-1 or PAI-1 siRNA. The expression level of PAI-1 in the fibroblasts was measured using real time RT-PCR and Western blot analysis. The fibroblast proliferation was evaluated using MTT assay. Results: Intratracheal injection of PAI-1 siRNA (7.5 nmoL/0.2 mL) significantly alleviated alveolitis and collagen deposition, reduced the expression of PAI-1, α-SMA, collagen type-I and collagen type-III, and increased the expression of caspase-3 in BLM-induced fibrotic lung tissue. In consistence with the in vivo results, the proliferation of the cultured fibroblasts from BLM-induced fibrotic lung tissue was inhibited by transfection with PAI-1 siRNA, and accelerated by overexpression of PAI-1 by transfection with pcDNA-PAI-1. The expression of caspase-3 was increased as a result of PAI-1 siRNA transfection, and decreased after transfection with pcDNA-PAI-1. In addition, the levels of p-ERK1/2 and PI3K/Akt in the fibrogenic lung tissue were reduced after treatment with PAI-1 siRNA.Conclusion: The data demonstrate that PAI-1 siRNA inhibits alveolitis and pulmonary fibrosis in BLM-treated rats via inhibiting the proliferation and promoting the apoptosis of fibroblasts. Suppression ERK and AKT signalling pathways might have at least partly contributed to this process. Targeting PAI-1 is a promising therapeutic strategy for pulmonary fibrosis.

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Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis

Cited by 31 publications

References 28 publications

Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model

Targeting Plasminogen Activator Inhibitor-1 Inhibits Angiogenesis and Tumor Growth in a Human Cancer Xenograft Model

Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

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