Loss of p16INK4a Results in Increased Glucocorticoid Receptor Activity during Fibrosarcoma Development

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-03, Vol.100 (6), p.3113-3118
• Main Authors: Roca, Ramon, Kypta, Robert M., Maria d. M. Vivanco
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological Sciences; Cell cycle; Cell Division - drug effects; Cell growth; Cell lines; Cells; Cyclin-Dependent Kinase Inhibitor p16 - deficiency; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclins; Dexamethasone - pharmacology; DNA; DNA Methylation; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; Exons; Fibrosarcoma - etiology; Fibrosarcoma - genetics; Fibrosarcoma - metabolism; Genes, p16; Methylation; Mice; Polymerase chain reaction; Precancerous Conditions - etiology; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Proteins; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Transcriptional Activation; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0634912100

Glucocorticoids inhibit proliferation of many cell types, but the relationship between the glucocorticoid receptor (GR) and the proteins regulating cell cycle progression is not fully understood. We previously found that during fibrosarcoma (FS) progression, GR displays only modest transcriptional activity in the preneoplastic stages, whereas it is highly active in FS cells. Now, we report that glucocorticoids reduce proliferation throughout FS development. The cyclin-dependent kinase inhibitor p16INK4a is frequently absent in many cancers, including FSs. We observed that p16INK4a protein expression is lost at the tumor stage of FS progression. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restores p16INK4a expression and reverts the phenotype of FS cells to low GR transcriptional activity, similar to that of the p16INK4a-expressing preneoplastic stages. Importantly, exogenous p16INK4a introduced by cotransfection is sufficient to reduce GR activity in FS cells, without affecting GR activity in p16-positive aggressive fibromatosis cells. Furthermore, GR transcriptional activity is elevated in mouse embryo fibroblasts derived from INK4a-/- mice compared with those derived from WT mice, implying that the difference in p16INK4a expression is sufficient to modulate GR activity. These results suggest a relationship between steroid hormone receptor activity and cell cycle inhibition, whereby absence of p16INK4a protein leads to higher GR transactivation activity and reduced cell sensitivity to dexamethasone. This observation might have important implications for current cancer therapies.