Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes

A Shirakami, T Toyonaga, K Tsuruzoe… - Journal of …, 2002 - joe.bioscientifica.com
A Shirakami, T Toyonaga, K Tsuruzoe, T Shirotani, K Matsumoto, K Yoshizato, J Kawashima…
Journal of Endocrinology, 2002joe.bioscientifica.com
Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors
(SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of
receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in
modulating receptor interactions in the androgen-dependent prostate cancer cell line,
LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and
immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their …
Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr 1 /sstr 2 , sstr 2 /sstr 5 , sstr 5 /dopamine (DA) type 2 receptor (D 2 R), and sstr 2 /D 2 R dimers. BIM-23704 (sstr 1 - and sstr 2 -preferential compound) increased the co-immunoprecipitation of sstr 1 /sstr 2 and significantly inhibited proliferation (−30.98%). BIM-23244 (sstr 2 –sstr 5 selective agonist) significantly increased the co-immunoprecipitation of sstr 2 /sstr 5 , and induced a −41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr 2 and D 2 R and a moderate affinity for sstr 5 , significantly increased the sstr 5 /D 2 R and sstr 2 /D 2 R complexes and was the most powerful in inhibiting proliferation (−42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D 2 R/sstr 5 and inhibiting cell proliferation (−30.54%). However, behind BIM-23A760, BIM-53097 (D 2 R-preferential compound) also significantly inhibited Calu-6 proliferation (−17.71%), suggesting a key role for D 2 R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.
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