Abstract
Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via retinoic acid receptor γ-mediated regulation of tumor cell transcription. Because topical retinoids can cause adverse cutaneous effects and because tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's antitumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anticancer effects.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Biomarkers, Tumor / genetics
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Carcinoma, Basal Cell / genetics
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Carcinoma, Basal Cell / pathology
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Carcinoma, Basal Cell / prevention & control*
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Cell Proliferation / drug effects
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / pathology
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Drug Resistance, Neoplasm / drug effects
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Enzyme Inhibitors / pharmacology
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Humans
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Keratolytic Agents / pharmacology
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Mice
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Nicotinic Acids / pharmacology
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Oligonucleotide Array Sequence Analysis
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Phosphatidylinositol 3-Kinases / genetics*
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Proto-Oncogene Proteins c-akt / genetics*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Retinoids / pharmacology*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Skin Neoplasms / prevention & control*
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Tumor Cells, Cultured
Substances
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Biomarkers, Tumor
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Enzyme Inhibitors
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Keratolytic Agents
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Nicotinic Acids
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RNA, Messenger
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Retinoids
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tazarotene
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt