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

doi:10.1038/sj.onc.1209065

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

Dermatology

Research output: Contribution to journal › Article › peer-review

55 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-x_L 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 language	English (US)
Pages (from-to)	378-386
Number of pages	9
Journal	Oncogene
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/sj.onc.1209065
State	Published - Jan 19 2006

Funding

We thank all members of the Skin Cancer Research Program for their help with this project, especially Jeffrey Panella for constructing the Ras (Q61) retroviral vector. We also thank Dr Divaker Choubey (Loyola University Medical Center, May-wood, IL, USA) for furnishing the Ras (Q61) cDNA, and Dr Norbert Fusenig (German Cancer Research Center, Heidelberg, Germany) and Mihaela Skobe (Harvard School of Medicine, Boston, MA, USA) for providing HaCaT cells and HaCaT Ras clones. This work was supported in part by a grant from the Potts Foundation (MFD), and NIH grants CA83784 (MFD) and AR47814 (BJN).

Keywords

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

ASJC Scopus subject areas

Genetics
Molecular Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.onc.1209065

Cite this

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

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.",

keywords = "Protein kinase C-δ, Skin cancer, Squamous cell carcinoma, Tumor suppressor gene",

author = "D'Costa, {A. M.} and Robinson, {J. K.} and T. Maududi and V. Chaturvedi and Nickoloff, {B. J.} and Denning, {M. F.}",

note = "Funding Information: We thank all members of the Skin Cancer Research Program for their help with this project, especially Jeffrey Panella for constructing the Ras (Q61) retroviral vector. We also thank Dr Divaker Choubey (Loyola University Medical Center, May-wood, IL, USA) for furnishing the Ras (Q61) cDNA, and Dr Norbert Fusenig (German Cancer Research Center, Heidelberg, Germany) and Mihaela Skobe (Harvard School of Medicine, Boston, MA, USA) for providing HaCaT cells and HaCaT Ras clones. This work was supported in part by a grant from the Potts Foundation (MFD), and NIH grants CA83784 (MFD) and AR47814 (BJN).",

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doi = "10.1038/sj.onc.1209065",

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AU - Chaturvedi, V.

AU - Nickoloff, B. J.

AU - Denning, M. F.

N1 - Funding Information: We thank all members of the Skin Cancer Research Program for their help with this project, especially Jeffrey Panella for constructing the Ras (Q61) retroviral vector. We also thank Dr Divaker Choubey (Loyola University Medical Center, May-wood, IL, USA) for furnishing the Ras (Q61) cDNA, and Dr Norbert Fusenig (German Cancer Research Center, Heidelberg, Germany) and Mihaela Skobe (Harvard School of Medicine, Boston, MA, USA) for providing HaCaT cells and HaCaT Ras clones. This work was supported in part by a grant from the Potts Foundation (MFD), and NIH grants CA83784 (MFD) and AR47814 (BJN).

PY - 2006/1/19

Y1 - 2006/1/19

N2 - 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.

AB - 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.

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KW - Squamous cell carcinoma

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ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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