Linch, M., Sanz-Garcia, M., Rosse, C., Riou, P., Peel, N., Madsen, C. D., Sahai, E., Downward, J., Khwaja, A., Dillon, C., Roffey, J., Cameron, A. J. M., Parker, P. J. (2014) Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids. CARCINOGENESIS, 35 (2). pp. 396-406. ISSN 0143-3334

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Abstract

Protein kinase C iota (PKC), a serine/threonine kinase required for cell polarity, proliferation and migration, is commonly up- or downregulated in cancer. PKC is a human oncogene but whether this is related to its role in cell polarity and what repertoire of oncogenes acts in concert with PKC is not known. We developed a panel of candidate oncogene expressing MadinDarby canine kidney (MDCK) cells and demonstrated that H-Ras, ErbB2 and phosphatidylinositol 3-kinase transformation led to non-polar spheroid morphogenesis (dysplasia), whereas MDCK spheroids expressing c-Raf or v-Src were largely polarized. We show that small interfering RNA (siRNA)-targeting PKC decreased the size of all spheroids tested and partially reversed the aberrant polarity phenotype in H-Ras and ErbB2 spheroids only. This indicates distinct requirements for PKC and moreover that different thresholds of PKC activity are required for these phenotypes. By manipulating PKC function using mutant constructs, siRNA depletion or chemical inhibition, we have demonstrated that PKC is required for polarization of parental MDCK epithelial cysts in a 3D matrix and that there is a threshold of PKC activity above and below which, disorganized epithelial morphogenesis results. Furthermore, treatment with a novel PKC inhibitor, CRT0066854, was able to restore polarized morphogenesis in the dysplastic H-Ras spheroids. These results show that tightly regulated PKC is required for normal-polarized morphogenesis in mammalian cells and that H-Ras and ErbB2 cooperate with PKC for loss of polarization and dysplasia. The identification of a PKC inhibitor that can restore polarized morphogenesis has implications for the treatment of Ras and ErbB2 driven malignancies.

Item Type:	Article
All Authors:	Linch, M., Sanz-Garcia, M., Rosse, C., Riou, P., Peel, N., Madsen, C. D., Sahai, E., Downward, J., Khwaja, A., Dillon, C., Roffey, J., Cameron, A. J. M., Parker, P. J.
Additional Information:	ISI Document Delivery No.: AA7IX Times Cited: 0 Cited Reference Count: 78 Linch, Mark Sanz-Garcia, Marta Rosse, Carine Riou, Philippe Peel, Nick Madsen, Chris D. Sahai, Erik Downward, Julian Khwaja, Asim Dillon, Christian Roffey, Jon Cameron, Angus J. M. Parker, Peter J. Cancer Research UK; Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre Cancer Research UK; Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre (M.L.). Oxford univ press Oxford
Uncontrolled Keywords:	prostate-cancer cells atypical pkc ras transformation in-vivo caenorhabditis-elegans proliferation control phospholipase-c tight junction breast-cancer tumor-growth
Research teams:	Clinical Units > Sarcoma Unit
Depositing User:	Alexander Smithson
Date Deposited:	20 Mar 2014 10:24
Last Modified:	20 Mar 2014 10:24
URI:	http://publications.icr.ac.uk/id/eprint/13116

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