Interestingly, we found that the combination of HT + metformin altered the phosphorylation pattern of different critical signalling pathways in PCa cells in a more pronounced way than the individual treatments with HT or metformin, including a further down-phosphorylation of ERK1 and ERK2 (from the MAPK pathway), P70S6K and 4E-BP1 (from the AKT pathway), as well as c-Fos, c-Jun, ATF2, and SMAD1/5 (from the TGF-b pathway). Here, SMAD1 is linked to posterior cortical atrophy.