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- Title
The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas.
- Authors
D'Costa, A. M.; Robinson, J. K.; Maududi, T.; Chaturvedi, V.; Nickoloff, B. J.; Denning, M. F.
- Abstract
Protein kinase C (PKC)-δ is proapoptotic in human keratinocytes, and is downregulated or inactivated in keratinocytes expressing the activated Ha-ras oncogene, making it a candidate tumor suppressor gene for squamous cell carcinoma (SCC). We evaluated the significance of PKC-δ loss in transformed human keratinocytes using tumorigenic HaCaT Ras II-4 cells that have significantly reduced PKC-δ levels. Re-expression of PKC-δ by retrovirus transduction caused an increase in apoptosis and growth inhibition in culture. The growth inhibition induced by PKC-δ could be partially reversed by Bcl-xL expression, indicating that apoptosis was in part responsible for PKC-δ-induced growth inhibition. PKC-δ re-expression suppressed the tumorigenicity of HaCaT Ras II-4 cells in nude mice (P<0.05), and the small tumors that did form contained elevated levels of activated caspase-3, indicating increased apoptosis. In addition, we found that 29% (12/42) of human Bowen's disease (squamous carcinoma in situ) or SCC cases had absent or reduced PKC-δ when compared to the surrounding normal epidermis. These results indicate that PKC-δ inhibits transformed keratinocyte growth by inducing apoptosis, and that PKC-δ may function as a tumor suppressor in human SCCs where its loss in cells harboring activated ras could provide a growth advantage by conferring resistance to apoptosis.Oncogene (2006) 25, 378–386. doi:10.1038/sj.onc.1209065; published online 12 September 2005
- Subjects
PROTEIN kinases; SQUAMOUS cell carcinoma; KERATINOCYTES; TUMOR suppressor proteins; TUMOR suppressor genes; CANCER treatment
- Publication
Oncogene, 2006, Vol 25, Issue 3, p378
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209065