Abstract
Castration-resistant prostate cancer (CRPC) is the lethal form of prostate cancer (PCa), and the underlying molecular mechanism has not been fully elucidated. Inositol requiring enzyme 1 alpha (IRE1α), a key regulator of unfolded protein response (UPR), is intimately associated with PCa progression. However, whether IRE1α is implicated in CRPC development remains unknown. Here, we showed that IRE1α expression was significantly increased in CRPC tissues and high-grade PCa tissues. Overexpression of IRE1α promoted PCa cell proliferation under the androgen deficiency condition in vitro and in vivo. Mechanistically, increased IRE1α expression induced IL-6 secretion via the IRE1α/XBP-1s signal pathway. IRE1α-induced IL-6 activated androgen receptor (AR), and the activation of AR by IL-6, in turn, promoted IRE1α expression. IRE1α formed a positive feedback loop with IL-6 and AR to promote prostate cancer cell proliferation under the androgen-deficient condition. In clinical PCa samples, high IRE1α expression correlated with elevated IL-6 and increased PSA expression. Our findings demonstrated a novel mechanism of CRPC progression and suggest targeting IRE1α may be a potential target for the prevention and treatment of CRPC.
Highlights
Prostate cancer (PCa) is the most common malignancy in men [1]
The IHC results showed that Inositol requiring enzyme 1 alpha (IRE1a) expression was significantly elevated in Castration-resistant prostate cancer (CRPC) tissues as compared to the hormone-naïve prostate cancers tissues and jacent normal tissues, the latter displayed comparably weak or negative IRE1a expression (Figures 1A, B)
The result showed that the expression of the IRE1a gene was significantly higher in CRPC than in primary prostate cancer or benign prostatic hyperplasia (Figure 1C). qPCR analysis on prostate cancer cell lines revealed that IRE1a presented higher mRNA levels in several androgen-independent prostate cancer cell lines C4-2B, PC3, and DU145, as compared to androgen-dependent prostate cancer cell lines LNCaP, LAPC-4, and VCaP (Figure 1D)
Summary
As for androgen-dependent cancer, androgen-receptor signaling plays a crucial role in PCa development and progression [2]. After the initial treatment response, a large number of patients will inescapably progress to castrate-resistant prostate cancer (CRPC), which is fatal and has no effective treatment. Extensive studies indicate that CRPC continues to rely on androgen receptor signals despite the availability of only castrate levels of androgens. Reactivation of the androgen receptor (AR) is still regarded as the leading cause of CRPC [3]. Mechanisms likely to be involved in the AR reactivation have been studied extensively but have failed to yield meaningful and useful targets [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
