The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors

Senthil Nathan Arun, Ding Xie, M. Ernest Dodd, Xiaofeng Zhong, Wendy B Bollag

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The serine/threonine kinase protein kinase D (PKD) has been proposed to be a pro-proliferative, anti-differentiative signal in epidermal keratinocytes. Indeed, the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) induces biphasic PKD activation, which mirrors the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes . in vitro and epidermis . in vivo. Objective: Our objective was to test the idea that PKD's pro-proliferative and/or anti-differentiative effects in keratinocytes contribute to TPA-induced tumorigenesis. Methods: Using western analysis and assays of keratinocyte proliferation and differentiation, we investigated the effect of inhibitors of PKD on keratinocyte function. Results: We found that overexpression of a constitutively active PKD mutant increased, and of a dominant-negative PKD mutant decreased, keratinocyte proliferation. A recently described selective PKD inhibitor showed low potency to inhibit keratinocyte proliferation or PKD activation. Therefore, we tested the ability of known only relatively selective PKD inhibitors on keratinocyte function and protein kinase activation. H89 {N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide}, a reported inhibitor of PKD and cAMP-dependent protein kinase, enhanced the effect of a differentiating agent on a marker of keratinocyte differentiation. Another reported non-selective PKD inhibitor, resveratrol stimulated differentiation and inhibited proliferation. The protein kinase C/PKD inhibitor Gö6976 blocked the increase in proliferation (as measured by DNA specific activity) induced by chronic TPA without affecting the initial TPA-elicited differentiation. Conclusion: Our results support the idea that relatively selective PKD inhibitors, such as Gö6976, H89 and resveratrol, might be useful for preventing/treating epidermal tumorigenesis without affecting keratinocyte differentiation.

Original languageEnglish (US)
Pages (from-to)29-39
Number of pages11
JournalJournal of Dermatological Science
Volume60
Issue number1
DOIs
StatePublished - Oct 1 2010

Fingerprint

Protein Kinase Inhibitors
Tumors
Keratinocytes
Tetradecanoylphorbol Acetate
Neoplasms
Acetates
Chemical activation
protein kinase D
Carcinogenesis
Protein-Serine-Threonine Kinases
Differentiation Antigens
Phorbol Esters
Cyclic AMP-Dependent Protein Kinases
Epidermis
Carcinogens
Protein Kinases
Protein Kinase C
Assays

Keywords

  • Keratinocytes
  • Protein kinase C (PKC)
  • Protein kinase D (PKD)
  • Resveratrol
  • Skin
  • Transglutaminase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology

Cite this

The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors. / Arun, Senthil Nathan; Xie, Ding; Dodd, M. Ernest; Zhong, Xiaofeng; Bollag, Wendy B.

In: Journal of Dermatological Science, Vol. 60, No. 1, 01.10.2010, p. 29-39.

Research output: Contribution to journalArticle

@article{920f35ebadd84815a490988c7f12e4d9,
title = "The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors",
abstract = "Background: The serine/threonine kinase protein kinase D (PKD) has been proposed to be a pro-proliferative, anti-differentiative signal in epidermal keratinocytes. Indeed, the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) induces biphasic PKD activation, which mirrors the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes . in vitro and epidermis . in vivo. Objective: Our objective was to test the idea that PKD's pro-proliferative and/or anti-differentiative effects in keratinocytes contribute to TPA-induced tumorigenesis. Methods: Using western analysis and assays of keratinocyte proliferation and differentiation, we investigated the effect of inhibitors of PKD on keratinocyte function. Results: We found that overexpression of a constitutively active PKD mutant increased, and of a dominant-negative PKD mutant decreased, keratinocyte proliferation. A recently described selective PKD inhibitor showed low potency to inhibit keratinocyte proliferation or PKD activation. Therefore, we tested the ability of known only relatively selective PKD inhibitors on keratinocyte function and protein kinase activation. H89 {N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide}, a reported inhibitor of PKD and cAMP-dependent protein kinase, enhanced the effect of a differentiating agent on a marker of keratinocyte differentiation. Another reported non-selective PKD inhibitor, resveratrol stimulated differentiation and inhibited proliferation. The protein kinase C/PKD inhibitor G{\"o}6976 blocked the increase in proliferation (as measured by DNA specific activity) induced by chronic TPA without affecting the initial TPA-elicited differentiation. Conclusion: Our results support the idea that relatively selective PKD inhibitors, such as G{\"o}6976, H89 and resveratrol, might be useful for preventing/treating epidermal tumorigenesis without affecting keratinocyte differentiation.",
keywords = "Keratinocytes, Protein kinase C (PKC), Protein kinase D (PKD), Resveratrol, Skin, Transglutaminase",
author = "Arun, {Senthil Nathan} and Ding Xie and Dodd, {M. Ernest} and Xiaofeng Zhong and Bollag, {Wendy B}",
year = "2010",
month = "10",
day = "1",
doi = "10.1016/j.jdermsci.2010.07.015",
language = "English (US)",
volume = "60",
pages = "29--39",
journal = "Journal of Dermatological Science",
issn = "0923-1811",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors

AU - Arun, Senthil Nathan

AU - Xie, Ding

AU - Dodd, M. Ernest

AU - Zhong, Xiaofeng

AU - Bollag, Wendy B

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Background: The serine/threonine kinase protein kinase D (PKD) has been proposed to be a pro-proliferative, anti-differentiative signal in epidermal keratinocytes. Indeed, the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) induces biphasic PKD activation, which mirrors the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes . in vitro and epidermis . in vivo. Objective: Our objective was to test the idea that PKD's pro-proliferative and/or anti-differentiative effects in keratinocytes contribute to TPA-induced tumorigenesis. Methods: Using western analysis and assays of keratinocyte proliferation and differentiation, we investigated the effect of inhibitors of PKD on keratinocyte function. Results: We found that overexpression of a constitutively active PKD mutant increased, and of a dominant-negative PKD mutant decreased, keratinocyte proliferation. A recently described selective PKD inhibitor showed low potency to inhibit keratinocyte proliferation or PKD activation. Therefore, we tested the ability of known only relatively selective PKD inhibitors on keratinocyte function and protein kinase activation. H89 {N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide}, a reported inhibitor of PKD and cAMP-dependent protein kinase, enhanced the effect of a differentiating agent on a marker of keratinocyte differentiation. Another reported non-selective PKD inhibitor, resveratrol stimulated differentiation and inhibited proliferation. The protein kinase C/PKD inhibitor Gö6976 blocked the increase in proliferation (as measured by DNA specific activity) induced by chronic TPA without affecting the initial TPA-elicited differentiation. Conclusion: Our results support the idea that relatively selective PKD inhibitors, such as Gö6976, H89 and resveratrol, might be useful for preventing/treating epidermal tumorigenesis without affecting keratinocyte differentiation.

AB - Background: The serine/threonine kinase protein kinase D (PKD) has been proposed to be a pro-proliferative, anti-differentiative signal in epidermal keratinocytes. Indeed, the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) induces biphasic PKD activation, which mirrors the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes . in vitro and epidermis . in vivo. Objective: Our objective was to test the idea that PKD's pro-proliferative and/or anti-differentiative effects in keratinocytes contribute to TPA-induced tumorigenesis. Methods: Using western analysis and assays of keratinocyte proliferation and differentiation, we investigated the effect of inhibitors of PKD on keratinocyte function. Results: We found that overexpression of a constitutively active PKD mutant increased, and of a dominant-negative PKD mutant decreased, keratinocyte proliferation. A recently described selective PKD inhibitor showed low potency to inhibit keratinocyte proliferation or PKD activation. Therefore, we tested the ability of known only relatively selective PKD inhibitors on keratinocyte function and protein kinase activation. H89 {N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide}, a reported inhibitor of PKD and cAMP-dependent protein kinase, enhanced the effect of a differentiating agent on a marker of keratinocyte differentiation. Another reported non-selective PKD inhibitor, resveratrol stimulated differentiation and inhibited proliferation. The protein kinase C/PKD inhibitor Gö6976 blocked the increase in proliferation (as measured by DNA specific activity) induced by chronic TPA without affecting the initial TPA-elicited differentiation. Conclusion: Our results support the idea that relatively selective PKD inhibitors, such as Gö6976, H89 and resveratrol, might be useful for preventing/treating epidermal tumorigenesis without affecting keratinocyte differentiation.

KW - Keratinocytes

KW - Protein kinase C (PKC)

KW - Protein kinase D (PKD)

KW - Resveratrol

KW - Skin

KW - Transglutaminase

UR - http://www.scopus.com/inward/record.url?scp=77957021002&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957021002&partnerID=8YFLogxK

U2 - 10.1016/j.jdermsci.2010.07.015

DO - 10.1016/j.jdermsci.2010.07.015

M3 - Article

C2 - 20832999

AN - SCOPUS:77957021002

VL - 60

SP - 29

EP - 39

JO - Journal of Dermatological Science

JF - Journal of Dermatological Science

SN - 0923-1811

IS - 1

ER -