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This version was published on December 1, 2006
Journal of Biomolecular Screening, Vol. 11, No. 8, 977-984 (2006)
DOI: 10.1177/1087057106292556

Identification of Novel Keratinocyte Differentiation Modulating Compounds by High-Throughput Screening

Masaru Honma

Keratinocyte Laboratory, Cancer Research UK London Research Institute, London

Mark Stubbs

Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom

Ian Collins

Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom

Paul Workman

Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom

Wynne Aherne

Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom

Fiona M. Watt

Keratinocyte Laboratory, Cancer Research UK London Research Institute, London

The authors have designed high-throughput screens to identify compounds that promote or inhibit terminal differentiation of primary human epidermal keratinocytes. Eleven known inhibitors of signaling pathways and approximately 4000 compounds of diverse structure were screened using an In-Cell Western system based on immunofluorescent staining of the terminal differentiation marker, involucrin. Staurosporine, a nonspecific protein kinase C inhibitor, and H89, a protein kinase A inhibitor, promoted expression of involucrin. Conversely, U0126, a MEK inhibitor, and SAHA or SBHA, 2 histone deacetylase inhibitors, reduced the expression of involucrin during calcium-induced stratification. In addition, the authors found 1 novel compound that induced keratinocyte differentiation and 2 novel compounds that were inhibitory to calcium-induced differentiation. The differentiation-inducing compound also inhibited growth of a human squamous cell carcinoma line by stimulating both differentiation and apoptosis. Because the compound affected the tumor cells at a lower concentration than primary keratinocytes, it may have potential as an antitumor therapy.

Key Words: keratinocyte • squamous cell carcinoma • differentiation • involucrin


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