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

• Published in: PloS one Vol. 16; no. 7; p. e0254315
• Main Authors: Jiang, Xiaolan, Renkema, Herma, Smeitink, Jan, Beyrath, Julien
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2021; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; CD44 antigen; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Cell self-renewal; Cold; Cyclooxygenases; Development and progression; Dinoprostone - metabolism; Drug therapy; Enzyme inhibitors; Feedback control; Flow cytometry; Gene Expression Regulation, Neoplastic - drug effects; Gene regulation; Head & neck cancer; Health aspects; Humans; Male; Medicine and Health Sciences; Metabolites; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Pancreatic cancer; Physiological aspects; Positive feedback; Prostaglandin E; Prostaglandin E2; Prostaglandin-E synthase; Prostaglandin-E Synthases - genetics; Prostaglandin-E Synthases - metabolism; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Research and analysis methods; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Transcription; Tumors; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0254315

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 PGE2, we found that the effect of KH176m on mPGES-1 expression and spheroid growth is due to the inhibition of a PGE2-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.