Sonlicromanol's active metabolite KH176m normalizes prostate cancer stem cell mPGES-1 overexpression and inhibits cancer spheroid growth

Aggressiveness of cancers, like prostate cancer, has been found to be associated with elevated expression of the microsomal prostaglandin E synthase-1 (mPGES-1). Here, we investigated whether KH176m (the active metabolite of sonlicromanol), a recently discovered selective mPGES-1 inhibitor, could affect prostate cancer cells-derived spheroid growth. We demonstrated that KH176m suppressed mPGES-1 expression and growth of DU145 (high mPGES-1 expression)-derived spheroids, while it had no effect on the LNCaP cell line, which has low mPGES-1 expression. By addition of exogenous PGE(2), we found that the effect of KH176m on mPGES-1 expression and spheroid growth is due to the inhibition of a PGE(2)-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Cancer stem cells (CSCs) are a subset of cancer cells exhibiting the ability of self-renewal, plasticity, and initiating and maintaining tumor growth. Our data shows that mPGES-1 is specifically expressed in this CSCs subpopulation (CD44(+)CD24(-)). KH176m inhibited the expression of mPGES-1 and reduced the growth of spheroids derived from the CSC. Based on the results obtained we propose selective mPGES-1 targeting by the sonlicromanol metabolite KH176m as a potential novel treatment approach for cancer patients with high mPGES-1 expression.

Automated summary

Aggressiveness of cancers, such as prostate cancer, is associated with elevated expression of mPGES-1. The selective mPGES-1 inhibitor KH176m can suppress the expression and growth of DU145-derived spheroids with high mPGES-1 expression, but has no effect on LNCaP cell line with low mPGES-1 expression. KH176m affects cell growth by inhibiting the PGE(2)-driven positive feedback control-loop of mPGES-1 transcriptional regulation.