Cellular clues to vitamin A resistance in lung cancer

Vitamin A deficiency has been associated with the development of lung cancer in laboratory studies. However, clinical trials of natural and synthetic derivatives of vitamin A, called retinoids, for the prevention of lung cancer have been largely unsuccessful in the general population.

A new study in the Journal of the National Cancer Institute finds that targeting a previously unknown variant of a common retinoid receptor may restore the beneficial effects of retinoids in lung cancer cells.

Retinoids help regulate certain cellular functions in the body, such as cell growth and differentiation. These effects are mediated by retinoic acid receptors (RARs), including RAR-beta. Clinical trials have supported a role for the use of retinoids in the prevention of aerodigestive tract cancers.

However, large randomized trials of retinoids and retinoic acid have shown that they are ineffective-and may even be harmful-in preventing lung cancer in smokers. Laboratory studies have found that, as lung cancer develops, RAR-beta becomes silenced, which makes cells resistant to retinoids. This loss of expression of RAR-beta is often seen in the lung cells of smokers.

W. Jeffrey Petty, M.D., previously of Dartmouth Medical School and now a faculty member of the Wake Forest University School of Medicine in Winston-Salem, N.C., and colleagues at Dartmouth set out to discover the mechanisms responsible for RAR-beta silencing and to see if they could restore the expression of RAR-beta using a compound called azacytidine. In the process of studying human bronchial epithelial cells that were resistant to treatment with retinoic acid, they discovered a previously unknown variant of one of the subtypes of RAR-beta.

The variant, called RAR-beta-1', was expressed in normal lung cells and in cells sensitive to retinoic acid, but not in cells that were resistant to retinoic acid treatment or in lung cancer cells. When they treated cancer cells with azacytidine, RAR-beta-2 expression-but not RAR-beta-1' expression-was restored, suggesting that the variant has characteristics and functions that are distinctly different from other known forms of RAR-beta and that it may play a role in retinoid resistance.

"Taken together, the data presented here directly implicate a critical role for RAR-beta-1' in mediating retinoid biologic effects in the lung and perhaps other organ sites," the authors write. "The frequent repression of RAR-beta-1' in lung carcinogenesis underscores its likely important biologic or clinical role. ? Identification of pharmacologic approaches that restore RAR-beta-1' expression would provide a basis for future retinoid-based combination strategies for lung cancer therapy or chemoprevention."

"The various isoforms of RAR-beta have complex relationships and interactions that appear to influence lung carcinogenesis, as illustrated by studies in mice and humans," Anita L. Sabichi, M.D., from the University of Texas M. D. Anderson Cancer Center in Houston, and colleagues write in an accompanying editorial. "The differential expression and effects of different RAR-beta isoforms are a potential area for molecular-targeted lung cancer chemoprevention, and targeting RAR-beta-1' to overcome retinoid resistance would be one potentially promising new approach."