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Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.

ABSTRACT: PURPOSE:Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation. EXPERIMENTAL DESIGN:The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] experiments. RESULTS:There was significant inhibition of ovarian cancer (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of proangiogenic cytokines in response to zoledronic acid treatment. Furthermore, zoledronic acid inactivated Rac1 and decreased the levels of Pak1/p38/matrix metalloproteinase-2 in ovarian cancer cells. In vivo, zoledronic acid reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when zoledronic acid was combined with nab-paclitaxel. CONCLUSIONS:Zoledronic acid has robust antitumor and antiangiogenic activity and merits further clinical development as ovarian cancer treatment.

SUBMITTER: Gonzalez-Villasana V

PROVIDER: S-EPMC4417466 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.

Gonzalez-Villasana Vianey V Fuentes-Mattei Enrique E Ivan Cristina C Dalton Heather J HJ Rodriguez-Aguayo Cristian C Fernandez-de Thomas Ricardo J RJ Aslan Burcu B Del C Monroig Paloma P Velazquez-Torres Guermarie G Previs Rebecca A RA Pradeep Sunila S Kahraman Nermin N Wang Huamin H Kanlikilicer Pinar P Ozpolat Bulent B Calin George G Calin George G Sood Anil K AK Lopez-Berestein Gabriel G

Clinical cancer research : an official journal of the American Association for Cancer Research 20150116 9

<h4>Purpose</h4>Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation.<h4>Experimental design</h4>The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] expe ...[more]

PMID: 25595279

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Project description:Background & aimsp21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/β-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice.MethodsIL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT.ResultsWhen compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased β-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation.ConclusionsPAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.

Dataset Information

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.

Publications

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.

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