PP2A promotes apoptosis and facilitates docetaxel sensitivity via the PP2A/p‑eIF4B/XIAP signaling pathway in prostate cancer

Abstract

Serine/threonine protein phosphatase 2A (PP2A) is a protein that has a wide range of biological functions. As prostate cancer progresses from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC), the expression level of PP2A has been found to decrease. The present study aimed to determine the roles that PP2A may play in prostate cancer and its association with the downstream factor, X-linked inhibitor of apoptosis (XIAP). First, the mRNA and protein expression levels of PP2A in LNCaP, DU145 and PC-3 prostate cancer cell lines were measured. Next, the population of PP2A heterodimers was increased using a PP2A agonist, DT061, in the DU145 and PC-3 cell lines. PP2A expression was then knocked down in the LNCaP cell line. Western blot analysis was performed to determine the association between PP2A, phosphorylated (p)-eukaryotic initiation factor 4B (eIF4B) and XIAP. The results revealed that following the increase in PP2A expression, the DU145 and PC-3 cell lines were more sensitive to docetaxel according to Cell Counting Kit-8 assays and had an increased apoptotic rate as assessed by flow cytometry. Conversely, following the transfection of small interfering (si)PP2A into the LNCaP cell line, the sensitivity to docetaxel decreased, as well as the apoptotic rate. In addition, following treatment with the PP2A agonist, DT061, PP2A expression was found to be significantly upregulated, while p-eIF4B and XIAP protein expression levels were significantly downregulated. By contrast, following the transfection of siPP2A into the LNCaP cell line, PP2A protein expression levels were found to be downregulated, while p-eIF4B and XIAP expression levels were significantly upregulated. In conclusion, by affecting the downstream factor XIAP, PP2A may play a key role in promoting apoptosis and facilitating docetaxel sensitivity in prostate cancer cell lines.

Secreted miR-210-3p, miR-183-5p and miR-96-5p reduce sensitivity to docetaxel in prostate cancer cells

“…In general, PP2A is considered a tumor suppressor and its dysregulation affects several physiological processes due to its involvement in most cellular pathways [ 44 ]. In particular, PP2A silencing in PCa cells has been shown to increase the expression of XIAP protein (via the PP2A/p-eIF4B/XIAP axis), which exerts its antiapoptotic effect by enhancing resistance to DCT [ 45 ]. Intriguingly, miR-1246, by directly targeting PPP2CB, impairs the function of the PP2A protein complex and leads to increased NF-kβ activity in mesenchymal stem/stroma cells [ 46 ].…”