Impairment of Retinoic Acid Receptor-Ceramide Signaling in Retinoic Acid-Resistant Breast Cancer Cells. Implications for Retinoid Differentiation Therapy of Breast Cancer
Poster
Data di Pubblicazione:
2003
Citazione:
Impairment of Retinoic Acid Receptor-Ceramide Signaling in Retinoic Acid-Resistant Breast Cancer Cells. Implications for Retinoid Differentiation Therapy of Breast Cancer / G. Somenzi, M. Ren, G. Sala, R. Ghidoni, N. Sacchi. - In: JOURNAL OF NUTRITION. - ISSN 0022-3166. - 133:11(2003 Nov 01), pp. 3852S-3853S. ((Intervento presentato al convegno International Research Conference on Food, Nutrition, and Cancer tenutosi a Washington D.C. nel 2003.
Abstract:
Despite promising preclinical animal studies, retinoic acid (RA),
the bioactive derivative of vitamin A, has given disappointing
results in clinical trials of human breast cancer because of the
hurdle of RA resistance. RA resistance seems to have an
heterogeneous molecular basis. One form of RA resistance in
breast cancer has been traced to epigenetic silencing of RA
receptors (RARs). In the breast cancer cell line T47D, RA
treatment (1 mmol/L, 72 h) induced impaired cell growth and
apoptosis concomitant with a 2.3-fold increase of endogenous
ceramide, a sphingolipid with a recognized role as proapoptotic
second messenger. In contrast, in the breast cancer cell line
MDA-MB-231 the same treatment failed to induce both growth
arrest and accumulation of proapoptotic ceramide. The two cell
lines differ in their RAR profiles in that T47D cells are RAR-a
positive and RAR-b inducible whereas MDA-MB-231 cells are
RAR-a and RAR-b negative. Thus we hypothesized that
ceramide accumulation may be mediated by RARs. To test this
hypothesis we engineered T47D cells to stably express an
RAR-a dominant-negative (DN) construct. DN T47D cells
present an RA-resistant phenotype and fail to accumulate
ceramide in response to RA treatment. In addition, by inhibiting
RAR-a in T47D cells with RAR-a antagonists, we observed
a failure to accumulate endogenous ceramide. Altogether these
data indicate that RA-induced ceramide in T47D cells is
mediated by RAR-a signaling. The synthetic retinoid fenretinide,
4-HPR, whose action is largely independent of RARs, was
able to induce cell death and a concomitant ceramide increase in
the MDA-MB-231 cell line, thus indicating that the biochemical
machinery required for endogenous ceramide production
is intact. In conclusion, we show that RA resistance
associated with a lack of functional RARs in breast cancer cells
can be overcome by using synthetic retinoids such as 4-HPR.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
G. Somenzi, M. Ren, G. Sala, R. Ghidoni, N. Sacchi
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