Curcumin and Oleocanthal Have Distinct Effects on Cell Signaling in Human NF1-Deficient Schwann Cells at Physiologically Relevant Doses
Neurofibromatosis Type 1 (NF1) is a cancer predisposition syndrome characterized by the inheritance of one loss of function allele of the NF1 gene. Schwann cell derived benign tumors called neurofibromas form in nearly all NF1 patients following the somatic biallelic loss of NF1. Plexiform neurofibromas, which develop in deep nerves, can progress to life-threatening malignant peripheral nerve sheath tumors (MPNSTs). The NF1 protein product, neurofibromin, negatively regulates the active form of RAS. Neurofibroma development and progression are driven by activated RAS signaling, especially the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, and an inflammatory microenvironment. A safe and effective chemopreventative approach for neurofibromas would be desirable for patients, and evidence exists that certain nutraceuticals could be effective. Turmeric derived curcumin and olive oil derived oleocanthal have anti-inflammatory properties and can suppress pro-growth signaling pathways relevant to neurofibromas. A curcumin and olive oil treatment seemed to shrink cutaneous and plexiform neurofibromas in a small NF1 clinical trial. However, the biochemical signaling effect of oleocanthal and curcumin in combination in NF1-deficient Schwann cells has not yet been explored. Here we show a significant decrease in mTOR signaling in Schwann cells treated with curcumin and oleocanthal in combination, regardless of NF1 presence, comparable to a specific mTOR inhibitor. The combination treatment also seemed to suppress p-ERK in certain NF1-deficient cells and p-STAT3 in benign Schwann cells. The combination of oleocanthal and curcumin shows promise as a potential chemopreventative treatment for decreasing tumor proliferative signaling in NF1 patients that could slow tumor growth and improve patient outcomes.