Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity

Abstract

We provide first-time evidence for ERβ-mediated transcriptional upregulation of c-FLIP as an underlying mechanism in the development of castrate-resistant cancer. While androgens inhibit apoptosis partly through transcriptional upregulation of the anti-apoptotic protein, c-FLIP in androgen-responsive cells, they downregulate c-FLIP in androgen-independent cells. We found that although Sp1 and p65 trans-activate c-FLIP, the combination of Sp1 and p65 has differential effects in a cellular context-dependent manner. We show that activation of the androgen metabolism enzyme, aldo-keto reductase, AKR1C1, relieves androgen independence through activation of 3β-Adiol-mediated upregulation of ERβ. ERβ competes with Sp1 and Sp3 to transcriptionally downregulate c-FLIP in the absence of consensus estrogen-response element in androgen-independent cells. Forced expression of AR in androgen-independent cells show that ERβ-mediated growth inhibition occurs under conditions of androgen independence. Reactivation of ERβ with the estrogenic metabolite, 2-methoxyestradiol, decreased enrichment ratio of Sp1/Sp3 at the c-FLIP promoter with concomitant effects on cell growth and death. Expression of Sp1 and c-FLIP are elevated while AKR1C1, ERβ and Sp3 are significantly low in human prostate tumor samples. ERβ is epigenetically silenced in prostate cancer patients, therefore our results suggest that combination of ERβ agonists with ADT would benefit men stratified on the basis of high estrogen levels.

Receptor tyrosine kinase recepteur d'origine nantais as predictive marker for aggressive prostate cancer in African Americans

“…Furthermore, levels of c‐FLIP are also elevated in human prostate tumors including castrate resistant tumors making it a clinically relevant target. Our findings that increased expression of AR, RON, and c‐FLIP in tumors is in line with published studies including our own . However, the present study to the best of our knowledge is the first report showing a correlation between RON/AR with ethnicity.…”

Sensing of Bacterial Cyclic Dinucleotides by the Oxidoreductase RECON Promotes NF-κB Activation and Shapes a Proinflammatory Antibacterial State

“…AKR1C1, also known as 20-alpha-hydroxysteroid dehydrogenase, is in the same subfamily as RECON and catalyzes the reaction of progesterone to the inactive form 20-alpha-hydroxyprogesterone. It has previously been shown to be important during pregnancy and in the development of some human cancers (Yun et al, 2015). It has ~70% identify with RECON and, similar to RECON, it is highly expressed in the liver, stomach and small intestine.…”

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

“…Primary PCa also demonstrates a selective loss of both AKR1C2 (16 fold) and AKR1C1 (2–4 fold) vs paired benign tissues [8, 26, 33, 34] as a consequence of this defect in DHT catabolism, DHT levels were significantly higher in primary PCa tumors [26]. In contrast, increased expression of HSD17B10 (3 fold), one of the oxidative enzyme capable of mediating the back conversion of 3α-diol to DHT, was observed in malignant epithelial cells compared to normal, which would also support an increased capacity to generate DHT in tumor tissue[35].…”

“…In PC-3 cells overexpression of AKR1C2 significantly decreased DHT-dependent AR reporter activity, which was abrogated by increasing DHT levels [8, 26]. DHT treatment was shown to induce AKR1C2 transcript in both DU145 and LNCaP cells, suggesting that a decrease in androgen levels might be countered by a decrease in AKR1C2-mediated catabolism of DHT to preserve DHT levels [8, 33]. …”