TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficient NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein, we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficient NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1-deficient NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach.

mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

“…Loss of TSC1/TSC2/TBC1D7 complex activity is related to mTORC1 hyperactivation, which characterizes TSC patients’ tissues, inducing several abnormalities in numerous cell biochemical processes such as the activation of transcription, translation and inhibition of autophagy. In accordance with this, numerous studies have revealed upregulation of mTORC1 in cellular and animal models of TSC and strongly indicated mTORC1 activation as the molecular bases of TSC pathology [ 66 , 67 , 68 , 69 ]. It is worth noting that the degree of mTORC1 activation correlates well with the severity of pathological symptom [ 70 ].…”

“…Recently, we demonstrate that TFEB activation restores Tsc1 -deficent neural stem/progenitor cell migration. In this work, we suggested TFEB as a druggable protein target for SEGAs therapy that can be used for an mTOR-independent approach [ 69 ].…”

Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells

“…TFEB overexpression also promotes tumorigenesis, angiogenesis, and metastasis by increasing lysosomal enzyme activity and the secretion of hydrolases into the extracellular space. By contrast, TFEB depletion reduces the migration of cancer cells . We showed that co‐treatment with vorinostat and melatonin reduced both nuclear localization and oligomerization of TFEB (Figure ), thereby inhibiting GBM tumorigenesis and tumor‐sphere formation by GSCs.…”

“…By contrast, TFEB depletion reduces the migration of cancer cells. 56 We showed that co-treatment with vorinostat and melatonin reduced both nuclear localization and oligomerization of TFEB (Figure 2), thereby inhibiting GBM tumorigenesis and tumor-sphere formation by GSCs.…”

Bioactivity Evaluation of a Novel Formulated Curcumin

“…In addition, curcumin can reverse multidrug resistance of cancer cells, suggesting that it can also serve as a supplement to traditional chemotherapy [9,10]. Several lines of evidence show that curcumin exerts potent anticancer effects against a broad range of human cancer cells, including prostate, colon, breast, ovarian, lung, and liver cancers, and can induce cancer cell apoptosis, for example, in liver cancer cell lines, including but not limited to HepG2, SK-Hep-1, Hep3B, SUN449, and Huh7 cells, with low cytotoxic effects on normal cells [11][12][13][14][15][16].…”