Ectopic expression of protein kinase C-β sensitizes head and neck squamous cell carcinoma to diterpene esters.
BACKGROUND
The objective of this study was to examine the effect of specific Protein kinase C (PKC) isoform re-expression in solid malignancies, particularly head and neck squamous cell carcinoma cell lines, and the impact this may have on treatment with known activators of PKC.


METHODS
The constitutive expression of PKC isoforms were determined in six head and neck squamous cell carcinoma (SCC) cell lines. Cytotoxicity of the prototypic phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) and the novel diterpene ester PEP005 was established. Viral transduction to re-express PKCβ isoforms in two of these cell lines was performed, and its effect on the sensitivity to the compounds was quantified.


RESULTS
Tongue and hypopharyngeal SCC cell lines were resistant to both TPA and PEP005, with the concentration required to inhibit growth by 50% (IC50) being >1,000 ng/ml. CAL-27 (tongue SCC) and FaDu (hypopharyngeal SCC) cell lines re-expressing PKCβI and -βII isoforms demonstrated IC50 of 1-5 ng/ml with TPA or PEP005.


CONCLUSIONS
Re-expression of PKCβ in head and neck SCC cell lines leads to cells one thousand-times more sensitive to the cytotoxic effects of phorbol or diterpene esters in culture. This highlights the importance of the isoform in tumor progression and presents the potential benefit of these compounds in malignancies expressing the protein, and in combination therapy.
Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Ryan A
RA
Adams
Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Marjorie M A
MM
D'Souza
Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Carly J
CJ
Pierce
Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Natasa
N
Korica
Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Ben
B
Wallwork
Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Peter G
PG
Parsons
Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Benedict
B
Panizza
Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Glen.Boyle@qimrberghofer.edu.au.
Glen M
GM
Boyle
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D064546:Protein Kinase C beta / Q000032:analysis / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004224:Diterpenes; D007527:Isoenzymes; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate
HNSCC; PEP005; Protein kinase C; TPA; diterpene