Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality.
Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical Compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP /GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy.
Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. a-yemelyanov@northwestern.edu
Alexander
A
Yemelyanov
Pankaj
P
Bhalla
Ximing
X
Yang
Andrey
A
Ugolkov
Kenichi
K
Iwadate
Apollon
A
Karseladze
Irina
I
Budunova
D000085:Acetates / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055550:Protein Stability; D011719:Pyrazines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015533:Transcriptional Activation; D014439:Tyramine / Q000031:analogs & derivatives / Q000494:pharmacology
C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001897:Boronic Acids; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D014439:Tyramine