bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021–07–25
fiveteen papers selected by
  1. Tsc1 regulates tight junction independent of mTORC1.
  2. TSC1/2 mutations-a unique type of mutation suitable for liver transplantation of Hepatocellular carcinoma.
  3. Histological Patterns of Skin Lesions in Tuberous Sclerosis Complex: A Panorama.
  4. Fetal Tuberous Sclerosis: Sirolimus for the Treatment of Fetal rhabdomyoma.
  5. Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs.
  6. Effects of Mutations in TSC Genes on Neurodevelopment and Synaptic Transmission.
  7. Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.
  8. The mTOR-Autophagy Axis and the Control of Metabolism.
  9. SAR1B senses leucine levels to regulate mTORC1 signalling.
  10. PPP1CA/YAP/GS/Gln/mTORC1 pathway activates retinal Müller cells during diabetic retinopathy.
  11. VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.
  12. Presynaptic GABAB receptor-mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice.
  13. Structural Aspects of mTOR Inhibitors: In Progress to Search Potential Compounds.
  14. Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.
  15. Corrigendum: Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.
  1. Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2020891118. [Epub ahead of print]118(30):
    Tsc1 regulates tight junction independent of mTORC1.
    Mingqiang Lai, Wenchong Zou, Zelong Han, Ling Zhou, Zeyou Qiu, Juan Chen, Sheng Zhang, Pinglin Lai, Kai Li, Yue Zhang, Li Liang, Yu Jiang, Zhipeng Zou, Xiaochun Bai.
      Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn's disease-like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn's disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.
    Keywords:  Myo6; Tsc1; cell adhesion; mTORC1; tight junction–related disease
    DOI:  https://doi.org/10.1073/pnas.2020891118
  2. J Gastrointest Oncol. 2021 Jun;12(3): 1074-1085
    TSC1/2 mutations-a unique type of mutation suitable for liver transplantation of Hepatocellular carcinoma.
    Jinming Wei, Linsen Ye, Laien Song, Hui Tang, Tong Zhang, Binsheng Fu, Yingcai Zhang, Qing Yang, Yang Yang, Shuhong Yi.
       Background: This study aimed to investigate the relationship between the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation and mammalian target of rapamycin (mTOR) pathway-related genes-TSC1/2.
    Methods: We retrospectively analyzed the clinical data of 46 patients who underwent liver transplantation for HCC and performed next generation sequencing to analyze the relationship between the efficacy of sirolimus after liver transplantation for HCC and mutations in mTOR pathway-related genes, especially tuberous sclerosis complex (TSC) mutations.
    Results: The average age of 46 patients with liver transplantation for HCC was 51±21 years. After surgery, 35 patients received an anti-rejection/anti-tumor regimen that included sirolimus, and 11 patients did not receive sirolimus. There was no significant difference in survival rate between the two groups (P=0.761). The gene sequencing results showed mTOR-related pathway mutations in 10 patients, of whom five (10.9%) had TSC1/2 mutations. Of the 35 patients using sirolimus, those with mTOR-related mutations had significantly better survival rates than patients without mTOR-related mutations (P=0.016).
    Conclusions: According to genetic sequencing results, a personalized treatment plan for specific genetic mutations should be selected in patients undergoing liver transplantation for HCC. Patients with mTOR-related gene mutations, especially TSC mutations, can gain significant benefits from the use of mTOR inhibitors such as sirolimus.
    Keywords:  Hepatocellular carcinoma (HCC); TSC gene mutation; liver transplantation; survival prognosis
    DOI:  https://doi.org/10.21037/jgo-20-378
  3. Dermatopathology (Basel). 2021 Jul 04. 8(3): 236-252
    Histological Patterns of Skin Lesions in Tuberous Sclerosis Complex: A Panorama.
    Marine Cascarino, Stéphanie Leclerc-Mercier.
      Tuberous Sclerosis Complex (TSC) is a multisystem genetic disease characterized by cutaneous and extracutaneous hamartomas. The diagnosis is based on the association of major and minor criteria, defined by a consensus conference updated in 2012. The clinical examination of the skin is crucial because seven diagnostic criteria are dermatological: four major (hypomelanotic macules, angiofibroma or fibrous cephalic plaques, ungual fibromas, shagreen patches) and three minor criteria (confetti skin lesions, dental enamel pits, intraoral fibromas). Skin biopsy is commonly performed to assert the diagnosis of TSC when the clinical aspect is atypical. Histopathology of TSC cutaneous lesions have been poorly reported until now. In this article, we review the histologic features described in the literature and share our experience of TSC skin biopsies in our pediatric hospital specialized in genetic disorders. Both hypomelanotic lesions and cutaneous hamartomas (angiofibroma/fibrous cephalic plaques, ungual fibromas, shagreen patches) are discussed, including the recent entity called folliculocystic and collagen hamartoma, with a special emphasis on helpful clues for TSC in such lesions.
    Keywords:  angiofibroma; confetti skin lesions; cutaneous hamartoma; folliculocystic and collagen hamartoma; forehead fibrous plaque; hypomelanotic lesions; shagreen patch; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/dermatopathology8030029
  4. Fetal Pediatr Pathol. 2021 Jul 19. 1-7
    Fetal Tuberous Sclerosis: Sirolimus for the Treatment of Fetal rhabdomyoma.
    Ana Dagge, Luísa Andrade Silva, Sofia Jorge, Estela Nogueira, Mónica Rebelo, Luísa Pinto.
       BACKGROUND: Sirolimus constitutes a safe and effective treatment for cardiac manifestations of tuberous sclerosis complex (TSC) in children but only four cases describing prenatal treatment of rhabdomyomas with mTOR inhibitors have been published.
    CASE: In this case, sirolimus was initiated at 26 weeks´ gestation in a pregnant woman with TSC with a fetus with a large rabdomyoma conditioning severe arrythmia. There was a significant reduction in the tumor size with ongoing treatment and a partial reversion of the arrythmia.
    CONCLUSION: m-TOR inhibitors can be considered for severe cases of fetal rhabdomyomas with poor prognosis given its potencial benefits.
    Keywords:  Tuberous sclerosis; fetal therapy; rhabdomyoma; sirolimus
    DOI:  https://doi.org/10.1080/15513815.2021.1948646
  5. Noncoding RNA. 2021 Jul 10. pii: 40. [Epub ahead of print]7(3):
    Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs.
    Daniela Cukovic, Shruti Bagla, Dylan Ukasik, Paul M Stemmer, Bhanu P Jena, Akshata R Naik, Sandeep Sood, Eishi Asano, Aimee Luat, Diane C Chugani, Alan A Dombkowski.
      Exosomes are a class of small, secreted extracellular vesicles (EV) that have recently gained considerable attention for their role in normal cellular function, disease processes and potential as biomarkers. Exosomes serve as intercellular messengers and carry molecular cargo that can alter gene expression and the phenotype of recipient cells. Here, we investigated alterations of microRNA cargo in exosomes secreted by epileptogenic tissue in tuberous sclerosis complex (TSC), a multi-system genetic disorder that includes brain lesions known as tubers. Approximately 90% of TSC patients suffer from seizures that originate from tubers, and ~60% are resistant to antiseizure drugs. It is unknown why some tubers cause seizures while others do not, and the molecular basis of drug-resistant epilepsy is not well understood. It is believed that neuroinflammation is involved, and characterization of this mechanism may be key to disrupting the "vicious cycle" between seizures, neuroinflammation, and increased seizure susceptibility. We isolated exosomes from epileptogenic and non-epileptogenic TSC tubers, and we identified differences in their microRNA cargo using small RNA-seq. We identified 12 microRNAs (including miR-142-3p, miR-223-3p and miR-21-5p) that are significantly increased in epileptogenic tubers and contain nucleic acid motifs that activate toll-like receptors (TLR7/8), initiating a neuroinflammatory cascade. Exosomes from epileptogenic tissue caused induction of key pathways in cultured cells, including innate immune signaling (TLR), inflammatory response and key signaling nodes SQSTM1 (p62) and CDKN1A (p21). Genes induced in vitro were also significantly upregulated in epileptogenic tissue. These results provide new evidence on the role of exosomes and non-coding RNA cargo in the neuroinflammatory cascade of epilepsy and may help advance the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy.
    Keywords:  epilepsy; exosome; microRNA; neuroinflammation; toll-like receptor; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/ncrna7030040
  6. Int J Mol Sci. 2021 Jul 06. pii: 7273. [Epub ahead of print]22(14):
    Effects of Mutations in TSC Genes on Neurodevelopment and Synaptic Transmission.
    Davide Bassetti, Heiko J Luhmann, Sergei Kirischuk.
      Mutations in TSC1 or TSC2 genes are linked to alterations in neuronal function which ultimately lead to the development of a complex neurological phenotype. Here we review current research on the effects that reduction in TSC1 or TSC2 can produce on the developing neural network. A crucial feature of the disease pathophysiology appears to be an early deviation from typical neurodevelopment, in the form of structural abnormalities. Epileptic seizures are one of the primary early manifestation of the disease in the CNS, followed by intellectual deficits and autism spectrum disorders (ASD). Research using mouse models suggests that morphological brain alterations might arise from the interaction of different cellular types, and hyperexcitability in the early postnatal period might be transient. Moreover, the increased excitation-to-inhibition ratio might represent a transient compensatory adjustment to stabilize the developing network rather than a primary factor for the development of ASD symptoms. The inhomogeneous results suggest region-specificity as well as an evolving picture of functional alterations along development. Furthermore, ASD symptoms and epilepsy might originate from different but potentially overlapping mechanisms, which can explain recent observations obtained in patients. Potential treatment is determined not only by the type of medicament, but also by the time point of treatment.
    Keywords:  GABA; development; excitation-to-inhibition balance; glutamate; neuronal network hyperactivity; synaptic transmission; tuberous sclerosis
    DOI:  https://doi.org/10.3390/ijms22147273
  7. CNS Drugs. 2021 Jul 17.
    Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.
    Laurent M Willems, Felix Rosenow, Susanne Schubert-Bast, Gerhard Kurlemann, Johann Philipp Zöllner, Thomas Bast, Astrid Bertsche, Ulrich Bettendorf, Daniel Ebrahimi-Fakhari, Janina Grau, Andreas Hahn, Hans Hartmann, Christoph Hertzberg, Frauke Hornemann, Ilka Immisch, Julia Jacobs, Karl Martin Klein, Kerstin A Klotz, Gerhard Kluger, Susanne Knake, Markus Knuf, Klaus Marquard, Thomas Mayer, Sascha Meyer, Hiltrud Muhle, Karen Müller-Schlüter, Felix von Podewils, Susanne Ruf, Matthias Sauter, Hannah Schäfer, Jan-Ulrich Schlump, Steffen Syrbe, Charlotte Thiels, Regina Trollmann, Adelheid Wiemer-Kruel, Bernd Wilken, Bianca Zukunft, Adam Strzelczyk.
       BACKGROUND: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder.
    OBJECTIVE: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient's perspective.
    METHODS: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC.
    RESULTS: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0-15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8-10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items 'tiredness', 'skin problems' and 'mouth/gum problems', which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE.
    CONCLUSIONS: From the patients' perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
    DOI:  https://doi.org/10.1007/s40263-021-00839-4
  8. Front Cell Dev Biol. 2021 ;9 655731
    The mTOR-Autophagy Axis and the Control of Metabolism.
    Nerea Deleyto-Seldas, Alejo Efeyan.
      The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.
    Keywords:  autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients
    DOI:  https://doi.org/10.3389/fcell.2021.655731
  9. Nature. 2021 Jul 21.
    SAR1B senses leucine levels to regulate mTORC1 signalling.
    Jie Chen, Yuhui Ou, Rong Luo, Jie Wang, Dong Wang, Jialiang Guan, Yi Li, Peixue Xia, Peng R Chen, Ying Liu.
      The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B-GATOR2-mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-021-03768-w
  10. Exp Eye Res. 2021 Jul 17. pii: S0014-4835(21)00269-4. [Epub ahead of print]210 108703
    PPP1CA/YAP/GS/Gln/mTORC1 pathway activates retinal Müller cells during diabetic retinopathy.
    Yang Guo, Xiaomin Cang, Linling Zhu, Manhui Zhu, Aihong Li, Zhenzhen Wang, Yuting Zhang, Xueqin Wang, E Song.
      Diabetic retinopathy (DR) is a vision-loss complication caused by diabetes with high prevalence. During DR, the retinal microvascular injury and neurodegeneration derived from chronic hyperglycemia have attracted global attention to retinal Müller cells (RMCs), the major macroglia in the retina contributes to neuroprotection. Protein Phosphatase 1 Catalytic Subunit Alpha (PPP1CA) dephosphorylates the transcriptional coactivator Yes-associated protein (YAP) to promote the transcription of glutamine synthetase (GS). GS catalyzes the transformation of neurotoxic glutamate (Glu) into nontoxic glutamine (Gln) to activate the mammalian target of rapamycin complex 1 (mTORC1), which promotes the activation of RMCs. In this study, in vitro MIO-M1 cell and in vivo mouse high-fat diet and streptozotocin (STZ)-induced diabetic model to explore the role of the PPP1CA/YAP/GS/Gln/mTORC1 pathway on the activation of MRCs during DR. Results showed that PPP1CA promoted the dephosphorylation and nuclear translocation of YAP in high glucose (HG)-exposed MIO-M1 cells. YAP transcribed GS in HG-exposed MIO-M1 cells in a TEAD1-dependent and PPP1CA-dependent way. GS promoted the biosynthesis of Gln in HG-exposed MIO-M1 cells. Gln activated mTORC1 instead of mTORC2 in HG-exposed MIO-M1 cells. The proliferation and activation of HG-exposed MIO-M1 cells were PPP1CA/YAP/GS/Gln/mTORC1-dependent. Finally, RMC proliferation and activation during DR were inhibited by the PPP1CA/YAP/GS/Gln/mTORC1 blockade. The findings supplied a potential idea to protect RMCs and alleviate the development of DR.
    Keywords:  Diabetic retinopathy (DR); Mammalian target of rapamycin complex 1 (mTOR 1); Protein phosphatase 1 catalytic subunit alpha (PPP1CA); Retinal Müller cells (RMCs)
    DOI:  https://doi.org/10.1016/j.exer.2021.108703
  11. Sci Rep. 2021 Jul 21. 11(1): 14827
    VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.
    Athina Ganner, Christina Gehrke, Marinella Klein, Lena Thegtmeier, Tanja Matulenski, Laura Wingendorf, Lu Wang, Felicitas Pilz, Lars Greidl, Lisa Meid, Fruzsina Kotsis, Gerd Walz, Ian J Frew, Elke Neumann-Haefelin.
      Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
    DOI:  https://doi.org/10.1038/s41598-021-94132-5
  12. Pflugers Arch. 2021 Aug;473(8): 1261-1271
    Presynaptic GABAB receptor-mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice.
    Davide Bassetti, Heiko J Luhmann, Sergei Kirischuk.
      The TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor-mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen.
    Keywords:  Autistic spectrum disorder; E/I ratio; Hyperexcitability; MTOR; Presynaptic tonic inhibition
    DOI:  https://doi.org/10.1007/s00424-021-02576-5
  13. Anticancer Agents Med Chem. 2021 Jul 20.
    Structural Aspects of mTOR Inhibitors: In Progress to Search Potential Compounds.
    Kamalpreet Kaur, Arjun Anant, Vivek Asati.
      mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1, mTORC2. It plays a crucial role in various fundamental cell processes like cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, Zotarolimus have been used popularly. Whereas, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors, their structure-activity relationship which may help scientists for the development of potent inhibitors against cancer.
    Keywords:  Anti-cancer; SAR; heterocyclic compounds; mTOR pathways; pyrimidine derivatives; triple-negative breast cancer
    DOI:  https://doi.org/10.2174/1871520621666210720121403
  14. Cell Death Dis. 2021 Jul 22. 12(8): 728
    Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.
    Xianfang Liu, Huiyuan Suo, Shengli Zhou, Zhenxing Hou, Mingqiang Bu, Xiuxiu Liu, Wei Xu.
      Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its antitumor effects in head and neck squamous cell carcinoma (HNSCC) by inducing intrinsic apoptosis through suppression of mTORC1. However, the detailed mechanism and biological significance of afatinib-induced autophagy in HNSCC remains unclear. In the present study, we demonstrated that afatinib induced mTORC1 suppression-mediated autophagy in HNSCC cells. Further mechanistic investigation revealed that afatinib stimulated REDD1-TSC1 signaling, giving rise to mTORC1 inactivation and subsequent autophagy. Moreover, ROS generation elicited by afatinib was responsible for the induction of the REDD1-TSC1-mTORC1 axis. In addition, pharmacological or genetic inhibition of autophagy sensitized HNSCC cells to afatinib-induced apoptosis, demonstrating that afatinib activated pro-survival autophagy in HNSCC cells. Importantly, in vitro and in vivo assays showed that afatinib caused enhanced apoptosis but weaker autophagy in stem-like HNSCC cells constructed by CDH1 knockdown. This suggested that blocking autophagy has the potential to serve as a promising strategy to target HNSCC stem cells. In conclusion, our findings suggested that the combination treatment with afatinib and autophagy inhibitors has the potential to eradicate HNSCC cells, especially cancer stem cells in clinical therapy.
    DOI:  https://doi.org/10.1038/s41419-021-04011-0
  15. Front Neuroanat. 2021 ;15 715363
    Corrigendum: Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.
    Lena H Nguyen, Angélique Bordey.
      [This corrects the article DOI: 10.3389/fnana.2021.664695.].
    Keywords:  GATOR1 complex; cortical development; epilepsy; focal cortical dysplasia; in utero electroporation; mTOR; neuron migration; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fnana.2021.715363
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