Prostate cancer expressing membrane-bound TGF-α induces bone formation mediated by the autocrine effect of prostaglandin E2 in osteoblasts

Abstract

Prostate cancer highly metastasizes to bone, and such cancer is associated with severe bone resorption and bone formation at the site of metastasis. Prostaglandin E₂ (PGE₂) promotes bone resorption in inflammatory diseases; however, the roles in prostate cancer-induced bone formation are still unclear. In the present study, we investigated the effects of membrane-bound TGF-α on prostate cancer-induced bone formation through autocrine PGE₂ signaling in osteoblasts. In the prostate cancer explant experiment into tibiae, injected prostate cancer cells induced bone formation with the increased expression of osteogenic genes, such as Runx2 and Wnt5a, and prostaglandin synthase Ptgs2. In osteoblasts, PGE₂ increased the number of calcified bone nodules with enhanced expression of Runx2 and Wnt5a. We also screened the factors involved in cancer progression, and 11 EGF family members were found to be expressed in the human prostate cancer cell line PC3. PC3 highly expressed amphiregulin, HB-EGF, and especially TGF-α. Treatment with recombinant TGF-α increased the Ptgs2 expression and PGE₂ production in osteoblasts, which promoted the formation of calcified bone nodules, suggesting that the interaction between PC3 and osteoblasts promoted PGE₂ production. In co-culture of osteoblasts and fixed PC3 cells, the phosphorylation of EGFR and ERK and subsequent Ptgs2 expression and PGE₂ production were increased, an effect that was attenuated by treatment with inhibitors of EGFR and ERK. These results indicate that membrane-bound TGF-α enhances ERK signaling while also inducing PGE₂-mediated bone formation in osteoblasts, thus suggesting that prostate cancer regulates both PGE₂-mediated bone resorption and bone formation at the site of bone metastasis of prostate cancer.

Keywords: Bone formation; Bone metastasis; Prostaglandin E(2); Prostate cancer; TGF-α.