Journal Article

Reduction of protein kinase C delta attenuates tenascin-C stimulated glioma invasion in three-dimensional matrix

Susobhan Sarkar and V. Wee Yong

in Carcinogenesis

Volume 31, issue 2, pages 311-317
Published in print February 2010 | ISSN: 0143-3334
Published online December 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp297
Reduction of protein kinase C delta attenuates tenascin-C stimulated glioma invasion in three-dimensional matrix

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The invasiveness of glioma cells, a major cause of mortality in malignant brain tumors, is mediated in part by the cellular microenvironment. We have reported that in a three-dimensional matrix of type 1 collagen (3D-CL) gel, the extracellular matrix protein tenascin-C (TN) increased the invasiveness of glioma cells through the downstream production of matrix metalloproteinase (MMP)-12. In the present study, we have investigated the signaling mechanisms involved in the TN-stimulated glioma invasiveness. We found that the pan protein kinase C (PKC) inhibitor, bisindolylmaleimide I, decreased TN-enhanced glioma invasion in 3D-CL. Calphostin C, an inhibitor of conventional and novel PKC isozymes, and the relatively selective PKCδ inhibitor rottlerin decreased TN-stimulated glioma invasiveness in a concentration- and time-dependent manner. These findings of the possible involvement of PKCδ was supported by its translocation from the cytosol to membrane fraction in 3D-CL gel supplemented with TN as detected by western blot assays and immunofluorescence microscopy and by elevation of PKCδ enzyme activity. Moreover, pharmacological blockade of PKCδ decreased MMP-12 levels and glioma invasiveness. Finally, small interfering RNA to PKCδ reduced TN-stimulated glioma invasiveness concurrent with decreased MMP-12 production. Our results implicate PKCδ as a therapeutic target to reduce MMP-12 expression and glioma invasiveness when tumor cells are stimulated by the TN-enriched glioma microenvironment.

Journal Article.  4888 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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