Search Results (2)

Osteoblastic bone metastases are commonly detected in patients with advanced prostate cancer (PCa) and are associated with an increased mortality rate. Dickkopf-1 (DKK-1) antagonizes canonical WNT/β-catenin signaling and plays a complex role in bone metastases. We explored the function of cancer cell-specific DKK-1 in PCa growth, metastasis, and cancer–bone interactions using the osteoblastic canine PCa cell line, Probasco. Probasco or Probasco + DKK-1 (cells transduced with human DKK-1) were injected into the tibia or left cardiac ventricle of athymic nude mice. Bone metastases were detected by bioluminescent imaging in vivo and evaluated by micro-computed tomography and histopathology. Cancer cell proliferation, migration, gene/protein expression, and their impact on primary murine osteoblasts and osteoclasts, were evaluated in vitro. DKK-1 increased cancer growth and stimulated cell migration independent of canonical WNT signaling. Enhanced cancer progression by DKK-1 was associated with increased cell proliferation, up-regulation of NF-kB/p65 signaling, inhibition of caspase-dependent apoptosis by down-regulation of non-canonical WNT/JNK signaling, and increased expression of epithelial-to-mesenchymal transition genes. In addition, DKK-1 attenuated the osteoblastic activity of Probasco cells, and bone metastases had decreased cancer-induced intramedullary woven bone formation. Decreased bone formation might be due to the inhibition of osteoblast differentiation and stimulation of osteoclast activity through a decrease in the OPG/RANKL ratio in the bone microenvironment. The present study indicated that the cancer-promoting role of DKK-1 in PCa bone metastases was associated with increased growth of bone metastases, reduced bone induction, and altered signaling through the canonical WNT-independent pathway. DKK-1 could be a promising therapeutic target for PCa. Full article

Previous studies revealed that phenylmethimazole (C10) inhibits IRF3 signaling, preventing dsRNA-induction of type 1 interferon gene expression, production, and downstream signaling. In the present study, we investigated the molecular basis for C10 inhibition of dsRNA-stimulated IRF3 signaling. IRF-3 Trans-AM assays were used to measure C10 effects on dsRNA induction of IRF3 DNA binding. Green fluorescent protein-labeled IRF3 was used to measure C10 effects on dsRNA-induced IRF3 nuclear translocation. Native PAGE, SDS PAGE, and western blotting were used to identify effects of C10 on IRF3 homodimer formation and phosphorylation, respectively. There was a significant impairment of dsRNA-induced IRF3 DNA binding activity in human embryonic kidney and pancreatic cancer cells with C10 treatment. C10 also blocked dsRNA-induced IRF3 nuclear translocation and homodimer formation without blocking serine 396 phosphorylation of IRF3. Together, these results indicate that C10 interferes with IRF3 signaling by blocking dsRNA-induced IRF3 homodimer formation, a prerequisite for nuclear translocation and DNA binding activities. Full article