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Published on: October 24, 2019
An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the
Jean-Simon Diallo1, Benjamin Péant, Laurent Lessard
1Centre de recherche du Centre hospitalier de l'Université de Montréal (CR-CHUM) and Institut du cancer de Montréal, Montreal, Quebec, Canada.
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.
Methods And 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).
Conclusion:
We conclude that resistance to IP6 can be linked to a ligand-independent AR function.
Insights
Inositol hexakisphosphate (IP6) shows anticancer effects in prostate cancer (PCa) cells. Resistance to IP6 is linked to androgen receptor (AR) expression, suggesting a ligand-independent AR function.
Area of Science:
- Phytochemical research
- Cancer biology
- Prostate cancer therapeutics
Background:
- Inositol hexakisphosphate (IP6) is a plant-derived compound with demonstrated anticancer properties.
- Limited research exists on IP6 efficacy across diverse prostate cancer (PCa) cell lines.
Purpose of the Study:
- To evaluate the efficacy of IP6 in a comprehensive panel of PCa cell lines.
- To investigate the role of androgen receptor (AR) status in modulating IP6 response.
Main Methods:
- Utilized WST-1 assays to assess cell viability and response to IP6.
- Employing stable AR expression in PC3 cells (PC3(AR)) and AR-targeting siRNA.
- Measured caspase-3 activation, DNA fragmentation, and expression of NF-kappaB and p53/E2F-responsive genes.
Main Results:
- IP6 demonstrated greater activity in AR-negative PCa cells compared to AR-positive cells.
- Stable AR expression in PC3 cells reduced sensitivity to IP6, an effect reversed by AR siRNA.
- AR expression significantly attenuated IP6-induced caspase-3 activation and DNA fragmentation.
- IP6-mediated upregulation of specific genes was diminished in AR-expressing cells.
Conclusions:
- Resistance to IP6 in PCa cells is associated with androgen receptor (AR) expression.
- This resistance appears to be mediated by a ligand-independent AR function.
