The role of TXNDC5 in castration-resistant prostate cancer—involvement of androgen receptor signaling pathway

Abstract

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1α in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.

Endoplasmic reticulum protein ERp46 in prostate adenocarcinoma

“…Knockdown of ERp46 demonstrated more significant results on tumor growth in vivo compared with overexpression, which may be due to an already robust expression level of ERp46 in the parental cells. Similar to the results of the present study, ERp46 overexpression also induced an increased tumor cell growth rate in human prostate adenocarcinoma LNCaP cells, in vitro and in vivo (8). This was revealed to be at least in part due to increased androgen receptor stability and signaling in the presence of increased ERp46 (8).…”

“…Similar to the results of the present study, ERp46 overexpression also induced an increased tumor cell growth rate in human prostate adenocarcinoma LNCaP cells, in vitro and in vivo (8). This was revealed to be at least in part due to increased androgen receptor stability and signaling in the presence of increased ERp46 (8). Accordingly, in the in vivo experiments of the present study, a significant reduction of PSA secretion, a potential indication of tumor volume, was identified following knockdown of ERp46 (Fig.…”

“…An increased protein expression level of ERp46 in human metastatic renal cell carcinoma has previously been demonstrated (2), while other studies have demonstrated increased ERp46 protein expression in non-small cell lung carcinoma (13), colorectal adenoma and carcinoma specimens (14), as well as in castration-resistant prostate tumor samples compared with specimens of hormone-naive prostate cancer (8). Similarly, the results of the present study support an association between ERp46 overexpression and prostate cancer aggressiveness.…”

“…ERp46 has a large number of other interacting partners as determined by previous proteomic and interactome studies (5–7); the majority of ERp46 interacting partners are involved in oxidoreductive reactions (5). Although little is known about ERp46′s biological function, it has previously been demonstrated to be highly overexpressed in castration-resistant prostate cancer compared with hormone naïve prostate cancer, and was revealed to interact with the androgen receptor in human prostate cancer LNCaP cells, which led to an increase in androgen receptor stability and signaling (8). …”

Label free quantitative proteomics reveals the role of miR-200b in androgen-independent prostate cancer cells

“…This kind of imperfect complementarity with target ensures that miRNAs have multiple intracellular targets that lead to amplification of the biological effects [6,7]. Thus, the exact role of miR-200b in AIPC remains unclear although a subsequent study demonstrated that miR-200b mediates HIF1α-induced TXNDC5 expression under ADT conditions [8].…”