CORRESPONDENCE

Re: Cyclin D1 Proteolysis: a Retinoid Chemoprevention Signal in Normal, Immortalized, and Transformed Human Bronchial Epithelial Cells

Herbert Yu

Correspondence to: Herbert (He) Yu, M.D., Ph.D., Section of Cancer Prevention and Control, Feist-Weiller Cancer Center, Louisiana State University Medical Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71104 (e-mail: hyu{at}lsumc.edu).

Retinoids are potent antiproliferative molecules with potential implications in cancer prevention. The report by Boyle et al. (1) provides new insights into the mechanism of retinoid-mediated suppression of cell proliferation. The experiments demonstrated that retinoids could reduce cyclin D1 levels in bronchial epithelial cells and that the effect was due to the increase in cyclin D1 proteolysis, mediated through the ubiquitin-proteasome pathway. This finding suggests that the antiproliferative effect of retinoids is directly linked to the degradation of cyclin D1. It is interesting that retinoids may also have an indirect impact on cellular levels of cyclin D1 because of their relationship with insulin-like growth factor-I (IGF-I).

In vitro studies have demonstrated that retinoids are able to increase the expression of insulin-like growth factor-binding protein-3 (IGFBP-3) (2,3), a specific binding protein for insulin-like growth factors (IGFs) including IGF-I and IGF-II. IGFs are known to be strong mitogens for a variety of normal and cancerous cells. The mitogenic action of IGF-I is involved in the action of cyclin D1. Cell culture experiments show that IGF-I is capable of stimulating the transcription and synthesis of cyclin D1, resulting in acceleration of cell cycle progression from G1 to S phase (4,5). This mitogenic action of IGF-I is mediated through a specific cell membrane receptor, IGF-I receptor (IGF-IR), which has tyrosine kinase activity. The binding of IGF-I to its receptor IGF-IR is modulated by six IGF-binding proteins. IGFBP-3 is one of the major IGF-binding proteins in serum and in many types of tissue. Since IGFBP-3 has higher binding affinity to IGF-I than does IGF-IR, the binding of IGFBP-3 to IGFs blocks the interaction between IGF-I and IGF-IR. As a result, IGFBP-3 suppresses the mitogenic action of IGF-I. Taken together, retinoid-stimulated expression of IGFBP-3 results in suppression of the mitogenic action of IGF-I, which in turn reduces the level of cyclin D1.

The study by Boyle et al. did show that the retinoid-induced decline in cyclin D1 was the result of proteasome-mediated proteolysis and that using calpain inhibitor I, a specific inhibitor for proteasome 26S, could abolish the effect of retinoids on cyclin D1 degradation. Another in vitro study using the breast cancer cell line MCF-7 demonstrated that levels of IGF-I were not affected by a synthetic calpain inhibitor, calpeptin (6). Despite these findings, there is still a lack of direct evidence to rule out the possible involvement of the IGF-I pathway in the decline of cyclin D1 synthesis. Since elevated serum levels of IGF-I have recently been found to be a potential risk factor for lung cancer (7), elucidating the role of IGF-I in retinoid-mediated suppression of bronchial cell proliferation will improve our understanding of the role of the IGF family in lung cancer, and may have an impact on lung cancer intervention, with the use of these molecules as preventive agents and as biomarkers for risk assessment or for surrogate end point.

EDITOR'S NOTE

Jay Boyle did not respond to Herbert Yu's correspondence.

REFERENCES

1 Boyle JO, Langenfeld J, Lonardo F, Sekula D, Reczek P, Rusch V, et al. Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells. J Natl Cancer Inst 1999;91:373-9.[Abstract/Free Full Text]

2 Adamo ML, Shao ZM, Lanau F, Chen JC, Clemmons DR, Roberts CT Jr., Insulinlike growth factor-I (IGF-I) and retinoic acid modulation of IGF-binding proteins (IGFBPs): IGFBP-2, -3, and -4 gene expression and protein secretion in a breast cancer cell line. Endocrinology 1992;131:1858-66.[Abstract]

3 Gucev ZS, Oh Y, Kelley KM, Rosenfeld RG. Insulin-like growth factor binding protein 3 mediates retinoid acid- and transforming growth factor ß2-induced growth inhibition in human breast cancer cells. Cancer Res 1996;56:1545-50.[Abstract]

4 Furlanetto RW, Harwell SE, Frick KK. Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. Mol Endocrinol 1994;8:510-7.[Abstract]

5 Dufourny B, Alblas J, van Teeffelen HA, van Schaik FM, van der Burg B, Steenbergh PH, et al. Mitogenic signaling of insulin-like growth factor I in MCF-7 human breast cancer cells requires phosphatidylinositol 3-kinase and is independent of mitogen-activated protein kinase. J Biol Chem 1997;272:31163-71.[Abstract/Free Full Text]

6 Shiba E, Kim SJ, Kambayashi J, Kawamura I, Lacey E, Manda T, et al. Mechanism of growth inhibition by calpain inhibitor in MCF-7 cells. Anticancer Res 1997;17:1919-23.[Medline]

7 Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control study. J Natl Cancer Inst 1999;91:151-6.[Abstract/Free Full Text]



             
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