Enzalutamide-Resistant Progression of Castration-Resistant Prostate Cancer Is Driven via the JAK2/STAT1-Dependent Pathway

Abstract

Previous studies showed that CXCR7 expression was upregulated after enzalutamide (ENZ) treatment, and an increased level of CXCR7 could increase the invasion, migration, and angiogenesis of castration-resistant prostate cancer (CRPC) cells. This study demonstrated that the levels of p-JAK2, p-STAT1, C-Myc, and VEGFR2 were significantly reduced after CCX771, a specific CXCR7 inhibitor, treatment. This effect further increased after the combination treatment of ENZ and CCX771. Then, we verified that targeting the inhibition of JAK2 or STAT1 could remarkably increase apoptosis and DNA damage and decrease the migration of CRPC cells. More importantly, the combination treatment of ENZ + JAK2/STAT1 led to much greater suppression than the single-agent treatment of JAK2 or STAT1. Subcutaneous CRPC xenograft tumor growth was also reduced by single-agent ENZ treatment and single-agent FLUD, a specific STAT1 antagonist, treatment; but much superior effect was elicited by the combination treatment of ENZ + FLUD. The proliferative indices significantly decreased following combination treatment in tumor tissues compared with control-treatment tissues and single-agent-treatment tissues. Our results demonstrated that CXCR7, which signifies an androgen receptor (AR)-independent signaling pathway, caused CRPC progression via the downstream JAK2/STAT1 signal transduction cascade. Combined inhibition targeting both the AR and JAK2/STAT1 resulted in substantial tumor suppression due to the reduction in DNA damage repair ability and increment in apoptosis.

Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells

“…On the other hand, inhibitors of WNT/ β -catenin (XAV-939), AKT (Capiversatib), HDAC (Panobinostat) and proteosome/NF κ B (Bortezomib) all demonstrated an inhibitory effect or trend on prostate regeneration (Figure 6J), implicating these pathways in driving L1 generation and L1 regenerative activities. We also find JAK/STAT, which has received a lot of attention recently in relation to advanced PCa lineage plasticity 78–80 , to be one of the pathways deregulated in L1; however, we do not see any deregulation or enrichment of Stat motifs with castration in our scATAC studies. Furthermore, STAT chromatin recruitment has not been demonstrated in any of the recent studies, leaving us to wonder how JAK/STAT may be regulating treatment-induced plasticity.…”

Potential Application of Leelamine as a Novel Regulator of Chemokine-Induced Epithelial-to-Mesenchymal Transition in Breast Cancer Cells

“…Furthermore, to confirm the relationship between MnSOD and CXCR7/4, we overexpressed MnSOD in breast cancer cells. Interestingly, overexpression of MnSOD was observed to increase the level of CXCR7/4, and it was found that the protein expression level of the JAK/STAT pathway increased upon stimulation by CXCR7/4 [ 53 , 54 ]. In addition, overexpression of MnSOD induced invasion and migration of breast cancer cells, which was observed to be inhibited by LEE.…”

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth

“…We have previously shown that MAPK inhibitors resensitize CXCR7 + CRPC to enzalutamide ( 20 ). Others have demonstrated that JAK2/STAT1 inhibition in combination with enzalutamide decreases the CXCR7-driven CRPC tumor growth ( 63 ). In the current work, we identify AURKA as a major mediator of CXCR7-driven PCa and show that AURKA inhibition reduces tumor growth.…”