Abstract
We have analysed the expression of three calcium-independent isoforms of protein kinase C (PKC), PKCδ, PKCε and PKCζ, in an in vitro model of colon carcinogenesis consisting of the nontumorigenic rat colonic epithelial cell line D/WT, and a derivative src-transformed line D/src. While PKCζ and PKCε showed similar protein levels, PKCδ was markedly decreased in D/src cells when compared to the D/WT line. To assess whether down-regulation of PKCδ was causally involved in the neoplastic phenotype in D/src cells, we prepared a kinase-defective mutant of PKCδ. Stable transfection of this sequence caused morphological and growth changes characteristic of partial transformation in D/WT cells. Moreover, to test whether PKCδ was involved in growth control and transformation in this model, we overexpressed PKCδ in D/src cells. Transfected cells underwent marked growth and morphological modifications toward the D/WT phenotype. In a late stage in culture, transfected cells ceased to proliferate, rounded up and degenerated into multinucleated, giant-like cells. We conclude that PKCδ can reverse the transformed phenotype and act as a suppressor of cell growth in D/src cells. Moreover, our data show that downregulation of this isoenzyme of PKC may cooperate in the neoplastic transformation induced by the src oncogene in D/WT cells.
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Acknowledgements
We thank Dr Harald Mischak for supplying a PKCδ cDNA. A Yamagiwa-Yoshida Memorial International Cancer Study Grant was awarded to GP for international collaboration with the Harvard School of Public Health. Research grants were issued to GP from Italian Consiglio Nazionale delle Ricerche (Progetto Finalizzato Biotecnologie 1998/99, Comitato Naz. Biotecnologie e Biologia Molecolare), Associazione Italiana per la ricerca sul cancro (1998 – 1999) and Ministero dell'Università e della Ricerca Scientifica e Tecnologica. This investigation was also supported in part by a Center Grant from the National Institute of Environmental Health Sciences (ES 00002). We are grateful to graduate student Aurora Badaloni for skillful assistance and to Ms Jean Foley for help in preparing the manuscript.
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Perletti, G., Marras, E., Concari, P. et al. PKCδ acts as a growth and tumor suppressor in rat colonic epithelial cells. Oncogene 18, 1251–1256 (1999). https://doi.org/10.1038/sj.onc.1202408
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DOI: https://doi.org/10.1038/sj.onc.1202408
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