Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS

Role of sst2 as a tumour suppresser

The purpose of the present study was to analyse whether somatostatin was able to inhibit the intracrine-induced growth of rat pancreatic cancer cells AR4-2J expressing the HMW FGF-2 of 210 aa. This cell line is characterized by a high expression of endogenous sst2.The FGF-2 isoform of 210 amino acids (HMW FGF-2) contains a nuclear localization sequence (NLS) and is targeted to the nucleus. This FGF-2 isoform allows cells to growth in low serum concentrations through still unknown mechanisms called intracrine regulations.

The existence of molecules acting as negative regulators of the intracrine-induced cell growth has not been explored. We demonstrated that in AR4-2J cells stably expressing HMW FGF-2, activation of the somatostatin receptor subtype sst2 by the somatostatin analogue RC-160 in serum-deprived medium inhibits the mitogenic effect of the HMW FGF-2, without affecting growth of control cells. The signaling pathway implicates GÑi/JAK2/SHP-1. The GÑi inhibitor pertussis toxin and the JAK2 inhibitor AG490 abrogate the inhibitory effect of RC-160 on HMW FGF-2-induced cell growth. Co-mmunoprecipitation studies demonstrate the constitutive association of JAK2 and SHP-1, and RC-160 induces a rapid activation of both proteins followed by the dissociation of the complex. AG490 prevents the RC-160 induced SHP-1 activation indicating the implication of JAK2 in this process. JAK2 and SHP-1 are immunoprecipitated with sst2 in basal conditions indicating the existence of a functional signaling complex at the receptor level.

In summary, these data provide the first evidence that:
- The intracrine-induced proliferation can be reversed by extracellular acting polypeptides such as somatostatin.
- Sst2 inhibits HMW FGF growth signaling by activating the JAK2/SHP-1 pathway in AR-42J cells.

We have showed that in vivo sst2 gene transfer results in a significant antitumor effect characterized by both an increase of apoptosis, and an inhibition of cell proliferation. The present study was conducted to identify antitumoral bystander mechanisms elicited by sst2 expression after in vivo sst2 gene transfer in nude mice bearing pancreatic carcinoma.

Powiązane informacje

Reported by

INSERM U151, Institut Louis Bugnard
CHU Rangueil, Bat L3
31403 Toulouse Cedex 4
Śledź nas na: RSS Facebook Twitter YouTube Zarządzany przez Urząd Publikacji UE W górę