Ryan A Adams1, Marjorie M A D'Souza2, Carly J Pierce2, Natasa Korica2, Ben Wallwork3, Peter G Parsons2, Benedict Panizza3, Glen M Boyle4. 1. 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. 2. Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 3. Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia. 4. Drug Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Glen.Boyle@qimrberghofer.edu.au.
Abstract
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. MATERIALS AND 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. CONCLUSION: 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. Copyright
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. MATERIALS AND 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. CONCLUSION: 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. Copyright
Authors: Jason K Cullen; Glen M Boyle; Pei-Yi Yap; Stefan Elmlinger; Jacinta L Simmons; Natasa Broit; Jenny Johns; Blake Ferguson; Lidia A Maslovskaya; Andrei I Savchenko; Paul Malek Mirzayans; Achim Porzelle; Paul V Bernhardt; Victoria A Gordon; Paul W Reddell; Alberto Pagani; Giovanni Appendino; Peter G Parsons; Craig M Williams Journal: Sci Rep Date: 2021-01-08 Impact factor: 4.379