Figure 7

MID1 is an upstream modulator of proliferation. MID1 enhances protein levels of PDPK-1 and AR, resulting in promotion of PI3K and AR signaling pathways. Moreover, PP2A, which inhibits Akt and mTOR signaling as well as androgen hormone production, similarly as the approved anti-prostate cancer drug abiraterone, is targeted for degradation by MID1, a process that can be inhibited by metformin. Moreover, MID1 can activate the survival factor NFκB via inhibition of PP2A. Thus, MID1 drives proliferation by enhancing respective proteins and hormones, however, there is a negative feedback loop between MID1 and AR: MID1 enhances AR post-transcriptionally, which then in the presence of androgens translocates to the nucleus and, acting as transcription factor, negatively regulates MID1 gene expression. Thus, androgen-ablation therapy could lead to an increase in MID1, which then promotes proliferation and paves the way for PCa progression.