Peroxiredoxin 4 Contributes To Radiation Resistance Of Prostate Cancer Cells Through The Activation Of The Pi3k/Akt Signaling Pathway.

The peroxiredoxin (Prx) family of proteins functions as major cellular antioxidants that mediate oxidative signaling under physiological conditions as well as scavenge extra hydrogen peroxide in the context of oxidative stress. Prx4 is one of Prx family members which is mainly localized in endoplasmic reticulum (ER), but can be also found in cytosol and extracellular space. In addition to its function as a peroxidase, Prx4 has a specific role in oxidative protein folding in ER. However, the specific function of Prx4 has not been well defined. Previous studies indicate that Prxs are frequently upregulated in various types of human cancer. However, the role of Prx4 in prostate cancer has not been well defined. The purpose of this study is to examine the expression of Prx4 in prostate cancer and to explore its functional significance in cancer radiation resistance and recurrence. Bioinformatic tools were used to evaluate genetic alterations of PRDX4 gene as well as the levels of its transcripts in prostate normal and cancer populations. Kaplan-Meier survival analysis was used to explore the association of Prx4 levels with the prognosis of prostate cancer patients. Western blot and immunohistochemistry were used to evaluate the expression of Prx4 protein in cell lines and patient specimens. Loss of Prx4 in cells was achieved by knock down using lentiviral shRNA or knockout using CRISPR-Cas9 techniques. Cell proliferation, survival, and protein profiler kinase arrays were used to examine the differences between control and Prx4-depleted cells with or without ionizing radiation. We demonstrated that PRDX4 gene is frequently amplified in prostate cancer and the level of its transcript is highly elevated. Patients with Prx4 at higher quartile have significantly reduced probability of survival compared with those in lower quartile. Prostate cancer cells express much higher levels of Prx4 than normal epithelial cells. Moreover, Prx4 is upregulated by the activation of AR-dependent signaling, and depletion of Prx4 sensitizes prostate cancer cells to radiation-induced cell death. Mechanistically, Prx4 contributes to prostate cancer radiation resistance through the activation of PI3K/AKT signaling pathway. A combination of bioinformatic, histochemical, cellular, and molecular methods reveals that Prx4 plays a critical role in prostate cancer cell proliferation, radio-resistance and reoccurrence. Citation Format: Na Ding, Hong Jiang, Pratik Thapa, Yanning Hao, Aziza Alshahrani, Shengming Yang, Vivek M. Rangnekar, Xiaoqi Liu, Qiou Wei. Peroxiredoxin 4 contributes to radiation resistance of prostate cancer cells through the activation of the PI3K/AKT signaling pathway [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-079.