Abstract 1603: The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line

Abstract

Abstract Osteoblastic bone metastasis is the predominant phenotype observed in advanced prostate cancer and is associated with high patient mortality and morbidity. WNT signaling is necessary for both bone formation and tumor progression. Dickkopf-1 (DKK-1), a secretory antagonist of the canonical WNT/β-catenin signaling pathway, plays a complex role in bone tumors since it can either promote or decrease tumor occurrence and metastasis. The present study explored the molecular role of DKK-1 in prostate tumor progression, metastasis, and tumor-bone interactions using the osteoblastic canine prostate cancer cell line, Probasco. Previously, we found that DKK-1 can inhibit bone mineralization of mouse calvaria by Probasco conditioned medium (CM). Now we stably expressed DKK-1 in Probasco cells (Probasco-DKK-1), which were injected into the tibias or left ventricle of athymic mice. Bone metastases were monitored by bioluminesent imaging, microCT, and histopathology. Our results showed that Probasco-DKK-1 bone metastases had increased tumor growth, increased osteoclastic bone resorption, and decreased intramedullary woven bone formation in vivo. In vitro, DKK-1 had an autocrine effect on Probasco cells, which altered the cell morphology, increased cell proliferation, and induced EMT. Mechanistically, DKK-1 had little effect on the canonical WNT/β-catenin signaling while dramatically down-regulated the non-canonical WNT/JNK signaling, which inhibited caspase-dependent apoptosis in Probasco-DKK-1 cells. To investigate the effect of Probasco-DKK-1 on bone cells, primary osteoblasts and osteoclasts were treated by CM collected from cancer cells. We found that DKK-1 did not inhibit the mineralization of osteoblasts nor stimulate the activity of osteoclasts directly, but the expression of RNAKL was significantly higher in Probasco-DKK-1 CM-treated osteoblasts. Therefore, the Probasco-DKK-1 cells enhanced the activity of osteoclasts indirectly via the regulation of osteoblasts, which induced bone resorption. In conclusion, we showed that DKK-1 promoted prostate tumor growth by stimulating cell proliferation and inhibiting apoptosis in a canonical WNT-independent manner and attenuated the osteoblastic activity of prostate cancer. These findings provide new insights into the molecular mechanisms of DKK-1 in tumor progression. Citation Format: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol. The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1603.