Nrf2 sensitizes prostate cancer cells to radiation via decreasing basal ROS levels

Abstract

Androgen deprivation therapy (ADT) was reported to lower basal ROS level in prostate cancer (PCa) and to sensitize PCa to radiation. We aimed to seek for the underlying molecular mechanism and to develop novel additive treatments to ADT in this regard. We simulated human androgen milieu in vitro and tested the ROS level in PCa cells undergoing ADT. We also tested the Nrf2 level in PCa cells with or without ADT. Genetic and pharmaceutical upregulation of Nrf2 was applied in vitro and in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without castration to investigate whether Nrf2 overexpression supplemented the effect of ADT in PCa. We first discovered that androgen deprivation increased basal ROS level in PCa cells with AR expression. We then found that genetic Nrf2 upregulation lowered basal ROS similar to ADT. Also, SFN sensitized PCa cell to radiation via upregulation of Nrf2. We then found that Nrf2 level in control TRAMP groups was lower than castration or SFN groups. The SFN treated TRAMP mice showed similar level of Nrf2 to castration. Genetic and pharmaceutical upregulation of Nrf2 lowered the ROS in PCa cells and sensitized PCa cells to radiation similar to ADT, implicating possible administration of SFN in place of ADT for PCa patients requiring radiotherapy.

Nuclear transcription factor Nrf2 suppresses prostate cancer cells growth and migration through upregulating ferroportin

“…Not surprisingly, previous studies also proved that Nrf2 plays a key role in the development of cancers [28–30], including prostate cancer [19, 31]. It seems that an increased expression of Nrf2 may suppress the proliferation and invasion abilities of prostate cancer cells [19, 32], which exactly agreed with the results of our present study.…”

“…Not surprisingly, previous studies also proved that Nrf2 plays a key role in the development of cancers [28–30], including prostate cancer [19, 31]. It seems that an increased expression of Nrf2 may suppress the proliferation and invasion abilities of prostate cancer cells [19, 32], which exactly agreed with the results of our present study. However, Raatikainen et al revealed that when the Nrf2 was increased, the biochemical recurrence-free survival would be shortened and the overall survival rate would be worse, indicating a worse prognosis of prostate cancer patients and enhanced proliferative and invasive abilities [33].…”

“…Previous studies have already addressed the importance of Nrf2 in prostate cancer therapy due to its ability to decrease basal reactive oxygen species and make patients more sensitive to radiation therapy [19]. Recently, studies have focused on its crucial role in iron metabolism.…”

Fractionated radiation exposure amplifies the radioresistant nature of prostate cancer cells

“…In particular, reduced susceptibility to ROS-induced cellular damage and efficient repair of radiation-induced DNA damage was proposed as an underlying mechanisms to the observed radioresistance of prostate cancer stem cells 55 . Lower ROS basal levels were associated with increased Nfr2 levels and radiosensitivity in prostate cancer cells 56 . Basal ROS levels were lower in WT-22Rv1, than in AMC-22Rv1 and RR-22Rv1 cells.…”

Modulation of inflammatory and hormonal parameters in response to testosterone therapy: Effects on the ventral prostate of adult rats

“…The NRF2 increased expression following TT is related to improved conditions of oxidative stress through reduced production of reactive oxygen species (Cheung et al, ). In prostate tumor cells, NRF2 up‐regulation is able to inhibit proliferation and invasion (Liu et al, ; Li et al, ), and becomes a new promising target for treating prostate cancer (Xue et al, ).…”