Inhibition of the PI3K/AKT signaling pathway blocks the oncogenic activity of TRIM26 in prostate cancer cells.

Abstract

Abstract: The tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase with strong oncogenic activity in various cancers. However, its role and molecular mechanism in prostate cancer (PCa) remain elusive. To clarify its role in promoting PCa progression, we evaluated TRIM26 expression in cells and clinical specimens using immunohistochemistry and found that TRIM26 was significantly upregulated in PCa tissue. Moreover, high TRIM26 levels predicted a poor prognosis in patients with PCa. Ectopic overexpression of TRIM26 increased PCa cell proliferation and migration, and this activity was suppressed by TRIM26 knockdown. Notably, TRIM26 activated both protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) and the epithelial-mesenchymal transition (EMT) signaling pathways in PCa cells. Consistent with these findings, TRIM26 knockdown led to decreased activation of these signals. Furthermore, the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway activated by TRIM26 was attenuated by the PI3K inhibitor S14161. Similarly, cisplatin, a commonly used anti-PCa drug, downregulated TRIM26 and AKT/mTOR activation, while TRIM26 overexpression reversed AKT/mTOR inactivation. Finally, this finding was also demonstrated TRIM26 expression strikingly promoted tumor growth and activated AKT/mTOR signaling in a PCa xenograft. In conclusion, TRIM26 drives PCa malignancy and may be an attractive target for PCa treatment.