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  • Thumbnail for Arginine Deprivation Affects mTORC1 Activation and Localization in Malignant Peripheral Nerve Sheath Tumors
    Arginine Deprivation Affects mTORC1 Activation and Localization in Malignant Peripheral Nerve Sheath Tumors by Merritt, Carly

    Malignant peripheral nerve sheath tumors (MPNSTs) are rare, but highly aggressive sarcomas that often occur in patients with neurofibromatosis type I (NF1). Currently, surgical resection is the only treatment, but it is largely ineffective, resulting in a five-year survival rate between 20 and 50 percent. While MPNSTs are genetically and molecularly heterogeneous, mTOR is almost universally overexpressed in this cancer. Targeting the localization and activation of the mTOR complex mTORC1 within this subset of tumors may offer a strong potential treatment. As arginine is implicated in both mTORC1 localization and activation, modulating arginine levels may serve to regulate mTORC1. Importantly, arginine succinate dehydrogenase 1 (ASS1), an enzyme necessary for arginine synthesis, is suppressed in most sarcomas, causing cells to become reliant on extracellular arginine. Arginine deiminase reverts extracellular arginine to citrulline, effectively making arginine inaccessible by cells lacking ASS1. In this study, we set out to determine how arginine deprivation affects mTORC1 activation and localization and the potential impacts of mTORC1 on cellular metabolism. Using ADI-PEG20, a pegylated arginine deiminase drug, we deprived MPNST cells of arginine in vitro. To determine whether ADI-PEG20 could be effective at depriving cells of arginine, we first examined expression of ASS1 in MPNSTs and found heterogeneous expression among established MPNST cell lines. We found that depleting MPNSTs of arginine by ADI-PEG20 affects mTORC1 activation; however, this was independent of ASS1 expression, in contrast to our initial hypothesis. Because mTORC1 potentially interacts with hexokinase II (HK-II), a metabolic regulator, we examined the effect of arginine deprivation on mTORC1 binding to HK-II. mTORC bound HK-II independent of ASS1 expression. However, inactive mTORC1 preferentially bound to HK-II over active mTORC1. Finally, we explored MPNST metabolism, because previous studies have implicated mTORC1 interaction with HK-II in a switch from a glycolytic to OXPHOS phenotype. We found that MPNSTs favor an OXPHOS phenotype, an unusual metabolism in cancers. This association between mTORC1, HK-II, arginine, and metabolism give preliminary data important in understanding this unique cancer’s metabolism and methods of survival and may help to develop a treatment targeting MPNSTs.