The effect of Telmisartan on collagen biosynthesis depends on the status of estrogen activation in breast cancer cells.
PPAR-gamma and estrogen receptor belong to a family of nuclear hormone receptors that were shown to affect transcriptional activity of each other. The angiotensin II type 1 receptor antagonist Telmisartan is a well known PPAR-gamma ligand. The effect of Telmisartan-induced PPAR-gamma activation on collagen biosynthesis was studied in the estrogen-dependent (MCF-7 cells expressing alpha and beta receptors) and estrogen-independent (MDA-MB 231, expressing only beta receptor) cell lines. We have found that the presence of estrogen in growth medium (2nM) augmented collagen biosynthesis in both cell lines. An addition to the growth medium of PPAR-gamma agonist, Telmisartan, but not rosiglitazone or clofibrat, other PPAR-gamma agonists, induced inhibition of collagen biosynthesis in MCF-7 cells, cultured in the presence of estrogen, while it had no effect on collagen biosynthesis in MDA-MB-231 cells. On the other hand, Telmisartan induced stimulation of collagen biosynthesis in MCF-7 cells cultured in the absence of estrogen (or in conditions of estrogen receptor removal by ICI 182-780-dependent degradation) and had no effect on similarly cultured MDA-MB-231 cells. The effect of Telmisartan on collagen biosynthesis was found specific for PPAR-gamma and not for angiotensin II type 1 since Losartan (specific antagonist of angiotensin II type 1 receptor) in the presence of estradiol did not induce inhibition of this protein in MCF-7 cells. The mechanism of the inhibition was found at the level of NF-kB (known inhibitor of collagen gene expression) and MAPK signaling. PPAR-gamma ligands stimulated expression of NF-kB, while they inhibited expression of p-38 but not ERK1/ERK2. The data suggest that the effect of Telmisartan on collagen biosynthesis in breast cancer cells depends on the status of estrogen receptor activation and the inhibitory effect of Telmisartan on the process requires functional alpha estrogen receptor.
Kociecka
Beata
B
Department of Medicinal Chemistry, Medical University of Bialystok, Bialystok, Poland.
Surazynski
Arkadiusz
A
Miltyk
Wojciech
W
Palka
Jerzy
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D004967:Estrogens; D047495:PPAR gamma; D003094:Collagen; D000077333:Telmisartan