Altered in vitro spreading and cytoskeletal organization in human glioma cells by downregulation of urokinase receptor

Chintala, Shravan K.; Mohanam, Sanjeeva; Go, Yoshinori; Venkaiah, Boyapati; Sawaya, Raymond; Gokaslan, Ziya L.; Rao, Jasti S.

doi:10.1002/(sici)1098-2744(199712)20:4<355::aid-mc5>3.0.co;2-i

Cited by 25 publications

(10 citation statements)

References 31 publications

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“…Whereas the mitogenic effects of uPA are widely known (25), the role of uPAR has not been as clearly delineated. In fact, some previous uPAR blocking studies using a specific monoclonal antibody or uPAR antisense reported no effect on uPA-induced proliferation, consistent with our current findings that uPA-induced kidney fibroblast proliferation is independent of uPAR expression (25,30,34). In fact, in the present study, the opposite response was observed, with either genetic uPAR deficiency or pretreatment with a uPAR-blocking antibody associated with higher rates of uPA-induced proliferation than with control wild-type fibroblasts.…”

Section: Discussionsupporting

confidence: 91%

Mitogenic Signaling of Urokinase Receptor–Deficient Kidney Fibroblasts

Zhang¹,

Cai²,

López-Guisa³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The urokinase receptor (uPAR) attenuates myofibroblast recruitment and fibrosis in the kidney. This study examined the role of uPAR and its co-receptor LDL receptor-related protein (LRP) in the regulation of kidney fibroblast proliferation and extracellular signal-regulated kinase (ERK) signaling. Compared with uPARϩ/ϩ cells, uPARϪ/Ϫ kidney fibroblasts were hyperproliferative. UPARϪ/Ϫ fibroblast proliferation was 60% inhibited by an ERK kinase inhibitor. LRP protein was reduced and extracellular accumulation of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) proteins were greater in uPARϪ/Ϫ cultures. Addition of functional uPA protein or LRP antisense RNA significantly increased ERK signaling and cell mitosis in both genotypes. Enhanced uPARϪ/Ϫ fibroblast proliferation was reversed by a recombinant nonfunctional uPA peptide. The density of cellbound fluor-uPA was similar between uPARϪ/Ϫ and uPARϩ/ϩ fibroblasts (78 Ϯ 6 versus 92 Ϯ 16 units). These data suggest that uPAR-deficient kidney fibroblasts express lower levels of its scavenger co-receptor LRP, resulting in greater extracellular accumulation of uPA and PAI-1. Enhanced proliferation of uPARϪ/Ϫ fibroblasts seems to be mediated by uPA-dependent ERK signaling via an alternative urokinase receptor.

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Section: Discussionsupporting

confidence: 91%

Mitogenic Signaling of Urokinase Receptor–Deficient Kidney Fibroblasts

Zhang¹,

Cai²,

López-Guisa³

et al. 2004

Journal of the American Society of Nephrology

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“…Dynamic alterations in the organization of the actin cytoskeleton play a critical role in tumor‐associated progression such as invasion and metastasis (Chintala et al. 1997, 1999).…”

Section: Resultsmentioning

confidence: 99%

Doublecortin induces mitotic microtubule catastrophe and inhibits glioma cell invasion

Santra

Roberts

et al. 2008

Journal of Neurochemistry

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Doublecortin (DCX) is a microtubule (MT) binding protein that induces growth arrest at the G2-M phase of cell cycle in glioma and suppresses tumor xenograft in immunocompromised hosts. DCX expression was found in neuronal cells, but lacking in glioma cells. We tested the hypothesis that DCX inhibits glioma U87 cell mitosis and invasion. Our data showed that DCX synthesizing U87 cells underwent mitotic MT spindle catastrophe in a neurabin II dependent pathway. Synthesis of both DCX and neurabin II were required to induce apoptosis in U87 and human embryonic kidney 293T cells. In DCX expressing U87 cells, association of phosphorylated DCX with protein phosphatase-1 (PP1) in the cytosol disrupted the interaction between kinesin-13 and PP1 in the nucleus and yielded spontaneously active kinesin-13. The activated kinesin-13 caused mitotic MT catastrophe in spindle checkpoint. Phosphorylated-DCX induced depolymerization of actin filaments in U87 cells, down-regulated matrix metalloproteinases-2 and -9, and inhibited glioma U87 cell invasion in a neurabin II dependent pathway. Thus, localization of the DCX-neurabin II-PP1 complex in the cytosol of U87 tumor cells inhibited PP1 phosphatase activities leading to antiglioma effects via (1) mitotic MT spindle catastrophe that blocks mitosis and (2) depolymerization of actin that inhibits glioma cell invasion.

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“…Our previous results have demonstrated the possible involvement of Ras-PI3k in the uPAR-mediated signaling cascade (9). We have shown that the absence of uPAR in human glioma cells leads to morphological changes associated with decreased spreading and a disorganized cytoskeleton resulting in altered cell morphology (10). Cathepsin B is known to be associated with uPAR and its integrin-mediated signaling ability (11).…”

Section: Introductionmentioning

confidence: 95%

Down-regulation of uPAR and Cathepsin B retards cofilin dephosphorylation

et al. 2006

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Abstract. Cathepsin B and uPAR play key roles in cancer cell migration and invasion. Here, we demonstrate that the simultaneous, siRNA-mediated down-regulation of uPAR and cathepsin B inhibits glioma cell migration and is accompanied by cytoskeletal condensation. We show that the dephosphorylation of cofilin is inhibited by the down-regulation of uPAR alone and, to a lesser extent, by the down-regulation of cathepsin B alone, and that the effect was much higher with the down-regulation of both molecules by pUC. Using FACS analysis and Western blotting for the · V ß 3 integrin heterodimer, we determined that down-regulating uPAR subsequently causes the down-regulation of the · V ß 3 integrin heterodimer. As evidenced by Western blot analysis of ERK1/2, pERK1/2, p38MAPK, p-p38MAPK, AKT, pAKT and PI3-k, the MEK and PI3-k pathways are inhibited. From cytoskeleton studies, we observed that the down-regulation of uPAR caused cytoskeletal condensation and that the simultaneous downregulation of uPAR and cathepsin B was even more effective at inducing cytoskeletal condensation than uPAR alone. Our results demonstrate the relevance of uPAR in cytoskeletal dynamics and the potential of uPAR and cathepsin B as targets in the treatment of malignant gliomas.

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Altered in vitro spreading and cytoskeletal organization in human glioma cells by downregulation of urokinase receptor

Cited by 25 publications

References 31 publications

Mitogenic Signaling of Urokinase Receptor–Deficient Kidney Fibroblasts

Mitogenic Signaling of Urokinase Receptor–Deficient Kidney Fibroblasts

Doublecortin induces mitotic microtubule catastrophe and inhibits glioma cell invasion

Down-regulation of uPAR and Cathepsin B retards cofilin dephosphorylation

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