Extracellular matrix components regulate ACTH production and proliferation in corticotroph tumor cells

The extracellular matrix (ECM) conveys signals through membrane receptors called integrins producing changes in cell morphology, proliferation, differentiation and apoptosis. Previous studies suggest that the ECM plays an important role in pituitary physiology and tumorigenesis. In the present work we studied for the first time the effects of fibronectin, laminin, collagen I and collagen IV on hormone secretion and cell proliferation in the corticotroph tumor cell line AtT-20 and in normal pituitary cells, examining the signal transduction mechanisms that mediate these effects. ACTH production in AtT-20 cells was inhibited by fibronectin, laminin and collagen I. A reporter construct with the POMC promoter showed similar results, indicating that the effects of the ECM take place at the level of POMC gene transcription. In contrast, ACTH production was not significantly altered in normal pituitary cells. AtT-20 cell proliferation was stimulated by collagen IV and fibronectin, but inhibited by collagen I and laminin. In parallel, the cell morphology was modified by the ECM. We found that the production of reactive oxygen species mediate the effects of laminin and collagen IV. On the other hand, the effect of fibronectin was mimicked by beta1-integrin and Rho activation. These results show for the first time that the ECM controls ACTH biosynthesis and proliferation in corticotroph tumor cells and suggest a role for the ECM in corticotroph adenoma development.