Dorsomorphin Suppresses EMT to Reduce AR‐Negative Prostate Cancer Metastasis by Synergistically Antagonizing JAK2/STAT3 and Gli2‐Independent Shh Activation

Prostate cancer is the most frequently diagnosed tumor of male reproductive system. Clinically, there is a lack of effective treatment drugs for prostate cancer. Previous studies have shown that AMPK inhibitor dorsomorphin was demonstrated to have potent antitumor effects. However, the effect of dorsomorphin on prostate cancer and its molecular mechanism are still unclear. In this study, the effects of dorsomorphin on the invasion and infiltration, epithelial-mesenchymal transition (EMT), and angiogenesis were investigated in two types of prostate cancer cells (DU145 and PC-3). In addition, nude mouse tumorigenic experiments were performed to confirm the antitumor effect of dorsomorphin. We found that dorsomorphin treatment concentration- and time-dependently inhibited the invasion and infiltration of DU145 and PC-3 cells. In addition, dorsomorphin reduced the expression levels of extracellular matrix components and angiogenesis-related proteins (HIF-1<i>α</i> and VEGF). Further study showed that dorsomorphin inhibited matrix deposition by antagonizing the EMT. Our results from nude mouse tumorigenic experiments further demonstrated dorsomorphin's tumor-growth inhibitory effect, whereas its antimetastatic potential is supported by in vitro invasion and EMT assays. Mechanistically, dorsomorphin treatment suppressed TGF-β1 expression and thereby inhibited the phosphorylation and nucleation of Smad2/3 signaling, which plays a key role in the regulation of EMT. Further study showed that dorsomorphin-triggered inactivation of JAK2/STAT3 and sonic hedgehog (Shh) signaling was involved in the inhibition of TGF-β1-mediated EMT. Interestingly, dorsomorphin inhibited the expression and nucleation of Gli1 and Gli3 but not affected the expression of Gli2. Thus, these findings reveal that the new mechanism of AMPK inhibitor dorsomorphin against prostate cancer metastasis is through synergistically antagonizing JAK2/STAT3 and Gli2-independent Shh activation.