The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas.
Protein kinase C (PKC)-delta 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-delta loss in transformed human keratinocytes using tumorigenic HaCaT Ras II-4 cells that have significantly reduced PKC-delta levels. Re-expression of PKC-delta by retrovirus transduction caused an increase in apoptosis and growth inhibition in culture. The growth inhibition induced by PKC-delta could be partially reversed by Bcl-x(L) expression, indicating that apoptosis was in part responsible for PKC-delta-induced growth inhibition. PKC-delta 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-delta when compared to the surrounding normal epidermis. These results indicate that PKC-delta inhibits transformed keratinocyte growth by inducing apoptosis, and that PKC-delta 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.
D'Costa
A M
AM
Cardinal Bernardin Cancer Center, Skin Cancer Research Program, Loyola University Medical Center, Maywood, IL 60153, USA.
Robinson
J K
JK
Maududi
T
T
Chaturvedi
V
V
Nickoloff
B J
BJ
Denning
M F
MF
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics; D002460:Cell Line; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000378:metabolism
D051745:Protein Kinase C-delta