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PPAR‐γ expression in pituitary tumours and the functional activity of the glitazones: evidence that any anti‐proliferative effect of the glitazones is independent of the PPAR‐γ receptor
Author(s) -
Emery Michelle N.,
Leontiou Chrysanthia,
Bonner Sarah E.,
Merulli Chiara,
Nanzer Alexandra M.,
Musat Madalina,
Galloway Malcolm,
Powell Michael,
Nikookam Khash,
Korbonits Márta,
Grossman Ashley B.
Publication year - 2006
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2006.02610.x
Subject(s) - rosiglitazone , medicine , endocrinology , thiazolidinedione , pioglitazone , peroxisome proliferator activated receptor , receptor , immunohistochemistry , pituitary gland , cell growth , biology , hormone , diabetes mellitus , type 2 diabetes , genetics
Summary Objective It has been reported that both normal pituitary and pituitary tumours express PPAR‐γ, a nuclear hormone receptor, the expression being more abundant in pituitary tumours, and that this is the basis for the reported antiproliferative effects of the thiazolidinedione, rosiglitazone, in animal models. However, the mechanisms for the responsivity to rosiglitazone have remained unclear. Design and measurements To investigate this further, ‘real‐time’ PCR was used to assess PPAR‐γ mRNA expression, and Western blotting and immunohistochemistry to study its protein expression, in 46 human pituitary tumours and normal pituitary tissue. Cell proliferation of the GH3 pituitary cell line was assessed by [ 3 H]‐thymidine‐incorporation after 48 h rosiglitazone and pioglitazone (10 −4 m – 10 −10 m ) treatment alone, or rosiglitazone in combination with the PPAR‐γ antagonist GW9662. Results PPAR‐γ mRNA and protein was found to be expressed in normal pituitary and was variably expressed in pituitary tumours, but were increased specifically in nonfunctioning pituitary adenomas. However, very little staining was observed with immunohistochemistry, with only occasional cell nuclei stained, and no difference was detectable between controls and tumours. Rosiglitazone at 10 −4 m and 10 −5 m concentrations inhibited cell proliferation (10 −4 m 14·0% ± 1·5% and 10 −5 m 67% ± 4%[mean ± SEM] vs Control 100% ± 3%, P < 0·0001) while lower concentrations showed no significant effect. Following withdrawal of rosiglitazone 10 −5 m , the cells fully recovered at a further 48 h, while lower doses showed a ‘rebound’ of stimulation. Pioglitazone was of similar potency to rosiglitazone in inhibiting proliferation. The PPAR‐γ antagonist did not show a significant reversal of the antiproliferative effect of rosiglitazone, and indeed suppressed proliferation on its own. Conclusions Our data suggest that the antiproliferative action of rosiglitazone is probably not via PPAR‐γ.