Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications

Subependymal giant cell astrocytomas (SEGAs) are rare brain tumors observed in 10-20% of patients with tuberous sclerosis complex (TSC) and are the major cause of morbidity in children and young adults with TSC. A disease is caused by mutations in one of two tumor suppressor genes TSC1 or TSC2, which result in enhancement of mTOR kinase activity, dysregulation of cell growth, abnormal differentiation and tumorigenesis. Signaling via mTOR participates in multifaceted cellular and genomic responses but its effectors in the brain are largely unknown. In the current study, we performed global gene expression analysis on SEGA and control brain samples to reveal alterations in gene expression due to mTOR dysfunction. We identified two sets of genes: involved in tumorigenesis (up-regulated) and the nervous system development (down-regulated) in SEGAs or SEGA-derived cell cultures when compared to the normal brain or cultured human astrocytes. Application of pharmacological inhibitor of mTOR signaling – rapamycin affected the expression of selected genes in SEGA-derived cell cultures demonstrating their dependence on mTOR signaling. Preliminary clinical trials with rapamycin in patients with inoperable SEGAs have shown slight tumor reduction. In this study, we demonstrate that pharmacological inhibition of both mTOR and ERK signaling pathways in SEGA cells is necessary to affect considerably their proliferation, size, morphology and migration. Our findings of novel genes related to mTOR dysfunction and involvement of mTOR and ERK signaling in pathobiology of SEGA cells, may provide explanation how these pathways contribute to tumor formation and neurological alterations associated with tuberous sclerosis complex

08 September 2010