Figure 4.

Metformin was shown to reduce cell growth and viability in distinct pituitary adenoma cell lines in vitro. Both AMPK-dependent and -independent actions are involved. Metformin induced AMPK phosphorylation and activation in AtT20 corticotroph cells and GH3 lacto-somatotroph cells. Metformin inhibited the IGF-1R/AKT/mTOR pathway in AtT20 cells, and selectively suppressed the EGF-induced mTOR/p70S6 kinase pathway activation in GH3 cells without affecting ERK1/2 phosphorylation downstream of the same growth factor receptor. The AMPK activation can cooperate to the mTOR pathway inhibition by metformin, but AMPK-independent actions cannot be ruled out. In GH3 cells, metformin was shown to reduce the activity of STAT3, while increasing the activity of ATF3, a transcription factor involved in the response to stress conditions. These actions were not AMPK-dependent. The JAK-STAT3 signaling pathway plays a role in tumor cell metabolic reprogramming, and cooperates with other factors to shift cell metabolism towards aerobic glycolysis. A possible functional interaction between metformin and adenylyl cyclase (AC)-activating stimuli was investigated in GH3 cells. No functional antagonism was seen. On the other hand, metformin tended to further increase CREB phosphorylation. The possible involvement of AMPK was not investigated.