LAUSR

Introduction Cancer cells are able to survive oxidative phosphorylation (OXPHOS) inhibition by up-regulation of glycolysis. Androgens stimulate glycolysis in prostate cancer cells through activation of the androgen receptor (AR). Here we hypothesise that androgens might help subsets of prostate cancer cells to survive OXPHOS inhibition. In addition, the combined androgen signalling and OXPHOS inhibition might pose synergistic anti-tumour effects in vitro. Material and methods The effects of suppressing OXPHOS with 100 ng/ml oligomycin in charcoal stripped serum media (CSS), before and after the addition of 40 ng/dl testosterone in VCAP, LNCaP, and LNCaP-C4-2B cells in vitro were evaluated. Tumour cell viability after 72 hours was estimated using MTT assay. Results and discussions The addition of 100 ng/ml oligomycin to VCAP cells in a steroid-depleted environment (CSS) dramatically decreased cell viability compared to CSS alone (p<0.001). The addition of castrate testosterone levels (40 ng/dl) increased tumour cell viability both with and without the concurrent OXPHOS suppression (p<0.001 for both). VCAP cells are androgen-sensitive and harbour AR amplification. In LNCaP cells the addition of 100 ng/ml oligomycin in CSS resulted in a remarkable reduction in cell viability compared to CSS alone (p<0.001). Testosterone at 40 ng/dl increased cell viability compared to CSS alone, both with and without the concurrent OXPHOS inhibition (p<0.001 for both). The experiments were repeated using LNCaP-C4-2B cells. LNCaP-C4-2B cells are isogenic to LNCaP cells, but show persistent AR-mediated transcription even in androgen-deprived conditions. We found that the addition of 100 ng/ml oligomycin in CSS caused a smaller decrease in cell viability compared to LNCaP cells. Addition of 40 ng/dl testosterone significantly decreased the anti-tumour effects of OXPHOS inhibition (p<0.001). These in vitro results generate the hypothesis that active AR signalling might be involved in resistance towards the antitumor effects of OXPHOS inhibition. Conclusion The combined androgen depletion and OXPHOS inhibition shows promising synergistic anti-tumour effects in vitro.