4-MU

The effects of hyaluronan (HA) in cancer are widely studied; however, the role of different molecular weight HA is poorly understood. Identifying novel proteins regulated by different molecular weight HA may highlight novel therapeutic targets. Proteomics analysis was performed to identify novel proteins regulated by different molecular weight HA (27, 183 and 1000 kDa) in ES‐2 ovarian cancer cells over‐expressing Notch3 intra‐cellular domain. Our analyses identified sphingosine kinase 1 (SPHK1), a novel protein regulated by 183‐ and 1000‐kDa HA. Utilising online databases and high‐grade serous ovarian cancer (HGSOC) patient tissue microarray cohorts, we assessed the relationship between SPHK1 expression and ovarian cancer metastasis, recurrence and patient outcome. We assessed the effects of the HA synthesis inhibitor 4‐methylumbelliferone (4‐MU) on SPHK1 expression in ovarian cancer cells and HGSOC patient tissues using ex vivo tissue explant assays. SPHK1 was significantly increased in ovarian cancer compared to normal tissues, elevated in metastatic and recurrent HGSOC tissues and associated with poor patient outcome. 4‐MU significantly inhibited SPHK1 expression in ovarian cancer cells (ES‐2, CaOV3 and A2780) and HGSOC patient tissues. This study highlights a link between HA and SPHK1 expression in ovarian cancer. Our findings confirm an adverse effect on ovarian cancer prognosis. SPHK1 constitutes a novel promising target against ovarian cancer that warrants further investigation.

Hyaluronic acid (HA) is the main structure-forming polymer of the extracellular matrix. HA metabolism plays an important role in intercellular interaction in healthy organism and in various pathologies. HA is synthesized by hyaluronan synthase (HAS); mammals have three highly homologous isoforms of this enzyme: HAS1, HAS2, and HAS3. No highly specific competitive inhibitors of HASs have been described so far. 4-Methylumbelliferone (4-MU), a natural coumarin compound, is commonly used to inhibit HA synthesis in vivo and in cell cultures. The review is focused on the molecular mechanisms underlying the therapeutic effects of 4-MU and discusses results of 4-MU application in tissue cultures and animal disease models, as well as in first clinical trials of this compound. It was found that along with receptors and transcription factors, one of the pharmacological targets of 4-MU is HAS2, which is most common isoform of HAS. Moreover, it is inhibition of HA synthesis that underlies the pharmacological effects of 4-MU in oncological, autoimmune, degenerative, and hypercompensated regenerative processes (fibrosis, scar formation). New clinical drugs based on specific HAS2 inhibitors will be the first-in-class compounds to treat a wide range of diseases.