Aims: Prostate cancer is a well-known aggressive malignant tumor in men with a high metastasis rate and poor prognosis. Adapalene (ADA) is a third-generation synthetic retinoid with anticancer properties. We investigated the anti-tumor activity and molecular mechanisms of ADA in the RM-1 prostate cancer cell line in vivo and in vitro.Methods: The effects of ADA on cell proliferation were estimated using the CCK-8 and colony formation assays. The wound-healing assay and the Transwell assay were employed to examine the migratory capacity and invasiveness of the cells. Flow cytometry was utilized to evaluate the cell cycle and apoptosis, and Western blotting analysis was used to assess the expression of the associated proteins. Micro-CT, histomorphological, and immunohistochemical staining were used to assess the effects of ADA on bone tissue structure and tumor growth in a mouse model of prostate cancer bone metastasis.Result: ADA dramatically inhibited cell proliferation, migration, invasiveness, and induced S-phase arrest and apoptosis. ADA also regulated the expression of S-phase associated proteins and elevated the levels of DNA damage markers, p53, and p21 after ADA treatment, suggesting that the anti-tumor effect of ADA manifests through the DNA damage/p53 pathway. Furthermore, we observed that ADA could effectively inhibited tumor growth and bone destruction in mice.Conclusion: ADA inhibited prostate cancer cell proliferation, elicited apoptosis, and arrested the cell cycle in the S-phase. ADA also slowed the rate of tumor growth and bone destruction in vitro. Overall, our results suggest that ADA may be a potential treatment against prostate cancer.

No abstract

Osteoblasts are the main functional cells of bone formation, and they are responsible for the synthesis, secretion, and mineralization of the bone matrix. Phosphatidylinositol‐3‐kinase/Akt is an important signaling pathway involved in the regulation of cell proliferation, death, and survival. Some studies have shown that 3‐phosphoinositide‐dependent protein kinase‐1 (PDK‐1) plays an important role in the phosphorylation of Akt. In the present study, an osteocalcin (OCN) promoter‐driven Cre‐LoxP system was established to specifically delete the PDK‐1 gene in osteoblasts. It was found that the size and weight of PDK‐1 conditional gene knockout (cKO) mice were significantly reduced. von Kossa staining and microcomputed tomography showed that the trabecular thickness, trabecular number, and bone volume were significantly decreased, whereas trabecular separation was increased, as compared with wide‐type littermates, which were characterized by a decreased bone mass. A model of distal femoral defect was established, and it was found that cKO mice delayed bone defect repair. In osteoblasts derived from PDK‐1 cKO mice, the alkaline phosphatase (ALP) secretion and ability of calcium mineralization were significantly decreased, and the expressions of osteoblast‐related proteins, runt‐related transcription factor 2, OCN, and ALP were also clearly decreased. Moreover, the phosphorylation level of Akt and downstream factor GSK3β and their response to insulin‐like growth factor‐1 (IGF‐1) decreased clearly. Therefore, we believe that PDK‐1 plays a very important role in osteoblast differentiation and bone formation by regulating the PDK‐1/Akt/GSK3β signaling pathway.