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Signaling and Regulation

Retinoic Acid Differentially Regulates Cancer Cell Proliferation via Dose-Dependent Modulation of the Mitogen-Activated Protein Kinase Pathway¹

¹ Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA and
² Division of Retinoid Research, Allergan, Irvine, CA

Requests for reprints: David L. Crowe, Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033. Phone: (323) 442-3170; Fax: (323) 442-2981.

The chemotherapeutic agent retinoic acid (RA) and its derivatives have been used to treat many tumor types. The antitumor effects of retinoids are in part due to their ability to inhibit proliferation of cancer cells. However, smokers receiving dietary vitamin A and ß carotene in chemoprevention studies had a higher incidence of lung cancer. These studies imply that lower doses of retinoids may have tumor-promoting activity. The effects of RA are mediated by a family of ligand-dependent transcription factors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXR). We examined the effects of low- and high-dose RA treatment on proliferation of human squamous cell carcinoma lines in vitro. Low concentrations of RA (20 nM) increased proliferation of SCC lines by epidermal growth factor (EGF) activation of the mitogen-activated protein kinase ERK1. These changes were accompanied by increased expression of S- and G₂ phase cyclins and cyclin-dependent kinases (cdk), increased Rb phosphorylation, and increased E2F-1 DNA binding activity. In contrast, higher doses of RA (40 nM to 1 µM) inhibited ERK1 expression, caused accumulation of G₁ phase cyclins and cdks, decreased Rb phosphorylation, and increased Rb/E2F-1 association. Overexpression of ERK1 or dominant negative ERK1 was sufficient to reproduce the effects of low- and high-dose RA, respectively. Treatment with receptor selective retinoids revealed that both RAR and RAR mediated the effects of RA on SCC lines. We concluded that low-dose RA induced proliferation by increased EGF signaling while higher concentrations inhibited cell division by decreasing ERK1 activation.

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