An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell lines.
BACKGROUND
Inositol hexakisphosphate (IP6) is a phytochemical exhibiting anticancer activity. Because few prostate cancer (PCa) cell lines have been used to study IP6, we assessed its efficacy in a panel of PCa cell lines.


RESULTS
Using WST-1 assays we observed that, although androgens did not modulate its efficacy, IP6 was more active in androgen receptor (AR) negative cells than in AR-positive cells. Stable expression of the AR in PC3 cells (PC3(AR)) decreased the response to IP6, which was reversed by an AR-targeting siRNA. Furthermore, AR expression in PC3 cells resulted in significantly reduced caspase-3 activation (P < 0.001) and DNA fragmentation (P < 0.05) in response to IP6. Similarly, although treatment with IP6 caused the upregulation of NF-kappaB-responsive (IkappaB-alpha, IRF-2) and p53/E2F-responsive genes (Puma, Noxa) in PC3 cells, this increase was reduced in PC3AR cells (P < 0.01).


CONCLUSIONS
We conclude that resistance to IP6 can be linked to a ligand-independent AR function.
Diallo
Jean-Simon
JS
Centre de recherche du Centre hospitalier de l'Université de Montréal (CR-CHUM) and Institut du cancer de Montréal, Montreal, Quebec, Canada.
Péant
Benjamin
B
Lessard
Laurent
L
Delvoye
Nathalie
N
Le Page
Cécile
C
Mes-Masson
Anne-Marie
AM
Saad
Fred
F
D000728:Androgens / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010833:Phytic Acid / Q000009:adverse effects* / Q000494:pharmacology; D011467:Prostate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000728:Androgens; D004273:DNA, Neoplasm; D050684:E2F Transcription Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D010833:Phytic Acid; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases