Down-regulation of Integrin αvβ3 Expression and Integrin-mediated Signaling in Glioma Cells by Adenovirus-mediated Transfer of Antisense Urokinase-type Plasminogen Activator Receptor (uPAR) and Sense p16 Genes

Yoshiaki Adachi, Sajani S. Lakka, Nirmala Chandrasekar, Niranjan Yanamandra, Christopher S. Gondi, Sanjeeva Mohanam, Dzeng H. Dinh, William C. Olivero, Meena Gujrati, Takashi Tamiya, Takashi Ohmoto, Gregory Kouraklis, Bharat Aggarwal, Jasti S. Rao

Research output: Contribution to journalArticle

Abstract

Interaction between the extracellular matrix and integrin receptors on cell surfaces leads not only to cell adhesion but also to intracellular signaling events that affect cell migration, proliferation, and survival. The vitronectin receptor αvβ3 integrin is of key importance in glioma cell biology. The expression of urokinase-type plasminogen activator receptor (uPAR) was recently shown to co-regulate with the expression of αvβ3 integrin. Moreover, restoration of the p16 protein in glioma cells inhibits the αvβ3 integrin-mediated spreading of those cells on vitronectin. Thus we hypothesized that adenovirus-mediated down-regulation of uPAR and overexpression of p16 might down-regulate the expression of αvβ3 integrin and the integrin-mediated signaling in glioma cells, thereby defeating the malignant phenotype. In this study, we used replication-deficient adenovirus vectors that contain either a uPAR antisense expression cassette (Ad-uPAR) or wild-type p16 cDNA (Ad-p16) and a bicistronic adenovirus construct in which both the uPAR antisense and p16 sense expression cassettes (Ad-uPAR/p16) are inserted in the El-deleted region of the vector. Infecting the malignant glioma cell line SNB19 with Ad-uPAR, Ad-p16, or Ad-uPAR/ p16 in the presence of vitronectin resulted in decreased αvβ 3 integrin expression and integrin-mediated biological effects, including adhesion, migration, proliferation, and survival Our results support the therapeutic potential of simultaneously targeting uPAR and p16 in the treatment of gliomas.

Original languageEnglish (US)
Pages (from-to)47171-47177
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number50
DOIs
StatePublished - Dec 14 2001

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Urokinase Plasminogen Activator Receptors
p16 Genes
Adenoviridae
Integrins
Glioma
Down-Regulation
Genes
Vitronectin
Integrin alphaVbeta3
Cytology
Cell adhesion
Cell Adhesion
Restoration
Cell Movement
Cell Biology
Cell Survival
Adhesion
Complementary DNA
Cells
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Down-regulation of Integrin αvβ3 Expression and Integrin-mediated Signaling in Glioma Cells by Adenovirus-mediated Transfer of Antisense Urokinase-type Plasminogen Activator Receptor (uPAR) and Sense p16 Genes. / Adachi, Yoshiaki; Lakka, Sajani S.; Chandrasekar, Nirmala; Yanamandra, Niranjan; Gondi, Christopher S.; Mohanam, Sanjeeva; Dinh, Dzeng H.; Olivero, William C.; Gujrati, Meena; Tamiya, Takashi; Ohmoto, Takashi; Kouraklis, Gregory; Aggarwal, Bharat; Rao, Jasti S.

In: Journal of Biological Chemistry, Vol. 276, No. 50, 14.12.2001, p. 47171-47177.

Research output: Contribution to journalArticle

Adachi, Y, Lakka, SS, Chandrasekar, N, Yanamandra, N, Gondi, CS, Mohanam, S, Dinh, DH, Olivero, WC, Gujrati, M, Tamiya, T, Ohmoto, T, Kouraklis, G, Aggarwal, B & Rao, JS 2001, 'Down-regulation of Integrin αvβ3 Expression and Integrin-mediated Signaling in Glioma Cells by Adenovirus-mediated Transfer of Antisense Urokinase-type Plasminogen Activator Receptor (uPAR) and Sense p16 Genes', Journal of Biological Chemistry, vol. 276, no. 50, pp. 47171-47177. https://doi.org/10.1074/jbc.M104334200
Adachi, Yoshiaki ; Lakka, Sajani S. ; Chandrasekar, Nirmala ; Yanamandra, Niranjan ; Gondi, Christopher S. ; Mohanam, Sanjeeva ; Dinh, Dzeng H. ; Olivero, William C. ; Gujrati, Meena ; Tamiya, Takashi ; Ohmoto, Takashi ; Kouraklis, Gregory ; Aggarwal, Bharat ; Rao, Jasti S. / Down-regulation of Integrin αvβ3 Expression and Integrin-mediated Signaling in Glioma Cells by Adenovirus-mediated Transfer of Antisense Urokinase-type Plasminogen Activator Receptor (uPAR) and Sense p16 Genes. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 50. pp. 47171-47177.
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abstract = "Interaction between the extracellular matrix and integrin receptors on cell surfaces leads not only to cell adhesion but also to intracellular signaling events that affect cell migration, proliferation, and survival. The vitronectin receptor αvβ3 integrin is of key importance in glioma cell biology. The expression of urokinase-type plasminogen activator receptor (uPAR) was recently shown to co-regulate with the expression of αvβ3 integrin. Moreover, restoration of the p16 protein in glioma cells inhibits the αvβ3 integrin-mediated spreading of those cells on vitronectin. Thus we hypothesized that adenovirus-mediated down-regulation of uPAR and overexpression of p16 might down-regulate the expression of αvβ3 integrin and the integrin-mediated signaling in glioma cells, thereby defeating the malignant phenotype. In this study, we used replication-deficient adenovirus vectors that contain either a uPAR antisense expression cassette (Ad-uPAR) or wild-type p16 cDNA (Ad-p16) and a bicistronic adenovirus construct in which both the uPAR antisense and p16 sense expression cassettes (Ad-uPAR/p16) are inserted in the El-deleted region of the vector. Infecting the malignant glioma cell line SNB19 with Ad-uPAR, Ad-p16, or Ad-uPAR/ p16 in the presence of vitronectin resulted in decreased αvβ 3 integrin expression and integrin-mediated biological effects, including adhesion, migration, proliferation, and survival Our results support the therapeutic potential of simultaneously targeting uPAR and p16 in the treatment of gliomas.",
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T1 - Down-regulation of Integrin αvβ3 Expression and Integrin-mediated Signaling in Glioma Cells by Adenovirus-mediated Transfer of Antisense Urokinase-type Plasminogen Activator Receptor (uPAR) and Sense p16 Genes

AU - Adachi, Yoshiaki

AU - Lakka, Sajani S.

AU - Chandrasekar, Nirmala

AU - Yanamandra, Niranjan

AU - Gondi, Christopher S.

AU - Mohanam, Sanjeeva

AU - Dinh, Dzeng H.

AU - Olivero, William C.

AU - Gujrati, Meena

AU - Tamiya, Takashi

AU - Ohmoto, Takashi

AU - Kouraklis, Gregory

AU - Aggarwal, Bharat

AU - Rao, Jasti S.

PY - 2001/12/14

Y1 - 2001/12/14

N2 - Interaction between the extracellular matrix and integrin receptors on cell surfaces leads not only to cell adhesion but also to intracellular signaling events that affect cell migration, proliferation, and survival. The vitronectin receptor αvβ3 integrin is of key importance in glioma cell biology. The expression of urokinase-type plasminogen activator receptor (uPAR) was recently shown to co-regulate with the expression of αvβ3 integrin. Moreover, restoration of the p16 protein in glioma cells inhibits the αvβ3 integrin-mediated spreading of those cells on vitronectin. Thus we hypothesized that adenovirus-mediated down-regulation of uPAR and overexpression of p16 might down-regulate the expression of αvβ3 integrin and the integrin-mediated signaling in glioma cells, thereby defeating the malignant phenotype. In this study, we used replication-deficient adenovirus vectors that contain either a uPAR antisense expression cassette (Ad-uPAR) or wild-type p16 cDNA (Ad-p16) and a bicistronic adenovirus construct in which both the uPAR antisense and p16 sense expression cassettes (Ad-uPAR/p16) are inserted in the El-deleted region of the vector. Infecting the malignant glioma cell line SNB19 with Ad-uPAR, Ad-p16, or Ad-uPAR/ p16 in the presence of vitronectin resulted in decreased αvβ 3 integrin expression and integrin-mediated biological effects, including adhesion, migration, proliferation, and survival Our results support the therapeutic potential of simultaneously targeting uPAR and p16 in the treatment of gliomas.

AB - Interaction between the extracellular matrix and integrin receptors on cell surfaces leads not only to cell adhesion but also to intracellular signaling events that affect cell migration, proliferation, and survival. The vitronectin receptor αvβ3 integrin is of key importance in glioma cell biology. The expression of urokinase-type plasminogen activator receptor (uPAR) was recently shown to co-regulate with the expression of αvβ3 integrin. Moreover, restoration of the p16 protein in glioma cells inhibits the αvβ3 integrin-mediated spreading of those cells on vitronectin. Thus we hypothesized that adenovirus-mediated down-regulation of uPAR and overexpression of p16 might down-regulate the expression of αvβ3 integrin and the integrin-mediated signaling in glioma cells, thereby defeating the malignant phenotype. In this study, we used replication-deficient adenovirus vectors that contain either a uPAR antisense expression cassette (Ad-uPAR) or wild-type p16 cDNA (Ad-p16) and a bicistronic adenovirus construct in which both the uPAR antisense and p16 sense expression cassettes (Ad-uPAR/p16) are inserted in the El-deleted region of the vector. Infecting the malignant glioma cell line SNB19 with Ad-uPAR, Ad-p16, or Ad-uPAR/ p16 in the presence of vitronectin resulted in decreased αvβ 3 integrin expression and integrin-mediated biological effects, including adhesion, migration, proliferation, and survival Our results support the therapeutic potential of simultaneously targeting uPAR and p16 in the treatment of gliomas.

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