The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas

A. M. D'Costa, J. K. Robinson, T. Maududi, V. Chaturvedi, B. J. Nickoloff, M. F. Denning*

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)378-386
Number of pages9
JournalOncogene
Volume25
Issue number3
DOIs
StatePublished - Jan 19 2006

Keywords

  • Protein kinase C-δ
  • Skin cancer
  • Squamous cell carcinoma
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    D'Costa, A. M., Robinson, J. K., Maududi, T., Chaturvedi, V., Nickoloff, B. J., & Denning, M. F. (2006). The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas. Oncogene, 25(3), 378-386. https://doi.org/10.1038/sj.onc.1209065