1. ¹Cardinal Bernardin Cancer Center, Skin Cancer Research Program, Loyola University Medical Center, Maywood, IL, USA
2. ²Department of Medicine, Skin Cancer Research Program, Loyola University Medical Center, Maywood, IL, USA
3. ³Department of Pathology, Skin Cancer Research Program, Loyola University Medical Center, Maywood, IL, USA

Correspondence: Dr MF Denning, Cardinal Bernardin Cancer Center, Room 304, Loyola University Medical Center, 2160 S First Avenue, Maywood, IL 60153, USA. E-mail: mdennin@lumc.edu

Received 5 April 2005; Revised 14 July 2005; Accepted 25 July 2005; Published online 12 September 2005.

Abstract

Protein kinase C (PKC)- 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- loss in transformed human keratinocytes using tumorigenic HaCaT Ras II-4 cells that have significantly reduced PKC- levels. Re-expression of PKC- by retrovirus transduction caused an increase in apoptosis and growth inhibition in culture. The growth inhibition induced by PKC- could be partially reversed by Bcl-x_L expression, indicating that apoptosis was in part responsible for PKC--induced growth inhibition. PKC- 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- when compared to the surrounding normal epidermis. These results indicate that PKC- inhibits transformed keratinocyte growth by inducing apoptosis, and that PKC- 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.