bims-tubesc 2022-01-09 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2022–01–09
nine papers selected by

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.
Long non-coding RNA ACTA2-AS1 inhibits the cisplatin resistance of non-small cell lung cancer cells through inhibiting autophagy by suppressing TSC2.
Diagnostic features of tuberous sclerosis complex: case report and literature review.
Blood pressure and glomerular filtration rate in youth with tuberous sclerosis complex.
Rhabdomyoma and Hypoplastic Left Heart Syndrome - Case Report of a Very Rare Combination.
Hyponatremia: A Tip of the Iceberg in the Late Diagnosis of Tuberous Sclerosis Associated With Lymphangioleiomyomatosis.
Restoration of mitophagy ameliorates cardiomyopathy in Barth syndrome.
mTOR as the therapeutic target of vascular proliferative diseases: past, present, and future.
mTORC1 Signaling Pathway Mediates Chronic Stress-Induced Synapse Loss in the Hippocampus.

Adv Biol Regul. 2021 Dec 06. pii: S2212-4926(21)00072-5. [Epub ahead of print] 100854

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma.

Meena Jhanwar-Uniyal, Jose F Dominguez, Avinash L Mohan, Michael E Tobias, Chirag D Gandhi.

  Aberrant signaling of mechanistic target of rapamycin (mTOR' aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). Glioblastoma mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. There complexes are named mTORC1 and mTORC2 and downstream activated substrate execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and it's analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin2 caused a concentration dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E-BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell proliferation and migration. Torin1 showed similar effects only at higher doses. Another small molecule compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. Torin1 suppressed phosphorylation of PRAS40Thr246, however Torin2 completely abolished it. XL388 treatment inhibited the phosphorylation of PRAS40Thr246 at higher doses only. These findings underscore the use of novel compounds in treatment of cancer. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways.

Keywords:  Glioblastoma; mTOR; mTORC1 mTORC2

DOI:  https://doi.org/10.1016/j.jbior.2021.100854
Cell Cycle. 2022 Jan 05. 1-11

Long non-coding RNA ACTA2-AS1 inhibits the cisplatin resistance of non-small cell lung cancer cells through inhibiting autophagy by suppressing TSC2.

XueHui Liu, XuFeng Zhang, ShuZhang Du.

  Long non-coding RNA (lncRNA) ACTA2-AS1 has been reported to play an important role in the progression of multiple human malignancies. The article aims to explore the role of ACTA2-AS1 on the cisplatin resistance of non-small cell lung cancer (NSCLC). RT-qPCR was performed to investigate the expression of ACTA2-AS1 in cisplatin-resistant NSCLC cell lines. Western blot was used to investigate the effects of ACTA2-AS1 on autophagy-related protein expression. RIP assay and RNA pull down were used to analyze the combination of ACTA2-AS1 and enhancer of zeste homolog 2 (EZH2), and CHIP was used to analyze the combination of tuberous sclerosis complex-2 (TSC2) gene promoter and Lys-27 of histone H3 (H3K27me3). In this study, ACTA2-AS1 was downregulated in cisplatin-resistant NSCLC cell lines. ACTA2-AS1 negatively regulated the cell viability and positively regulated the cell apoptosis of cisplatin-resistant NSCLC cell lines. Furthermore, our results demonstrated that ACTA2-AS1 promoted cisplatin-resistant NSCLC cells apoptosis through inhibiting autophagy. The regulation of ACTA2-AS1 to the cisplatin-resistant NSCLC cell autophagy was reversed by TSC2 increasing. Importantly, our results displayed that ACTA2-AS1 bound with EZH2, and TSC2 gene promoter combined with H3k27me3. The inhibition of ACTA2-AS1 to TSC2 expression was recused by EZH2 silencing. In conclusion, ACTA2-AS1 inhibited the cisplatin resistances of NSCLC cell lines through suppressing TSC2 expressing by recruiting EZH2 to TSC2 gene promoter.

Keywords:  ACTA2-AS1; autophagy; cisplatin resistance; non-small cell lung cancer; tuberous sclerosis complex-2

DOI:  https://doi.org/10.1080/15384101.2021.2020433
Quant Imaging Med Surg. 2022 Jan;12(1): 846-861

Diagnostic features of tuberous sclerosis complex: case report and literature review.

Sultan Abdulwadoud Alshoabi, Abdullgabbar M Hamid, Fahad H Alhazmi, Abdulaziz A Qurashi, Osamah M Abdulaal, Khaled M Aloufi, Tareef S Daqqaq.

  Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic syndrome that is caused by mutations in the tumour suppressor genes TSC1 or TSC2 which causes multiorgan growths. TSC presents at any age as a wide range of clinical and phenotypic manifestations with varying severity. The main goal of this article was to state two cases of TSC and review the most commonly reported major and minor diagnostic clinical features and the most common features that led to an investigation of possible TSC diagnosis. Herein, we report two cases of TSC, which both presented with seizures during the first 6 months of life. Case 1 presented with multiple types of seizures from 6 months of age and was diagnosed by multiple calcified subependymal nodules (SENs) detected by computed tomography and magnetic resonance imaging (MRI). Case 2 presented with seizures from 3 months of age and was diagnosed prenatally when a tumour was seen in her heart during antenatal ultrasonography. In conclusion, the literature review revealed that neurological manifestations (mainly seizures) were the main feature that led to investigation and diagnosis of TSC followed by abdominal manifestations (mainly renal features) and antenatal follow-up imaging. Other manifestations in skin, chest, eyes, teeth and heart rarely led to TSC diagnosis. In some cases, TSC was incidentally discovered by medical imaging. The cortical tubers, SENs, and subependymal giant cell astrocytomas brain lesions were the most commonly reported major features. Skin features including angiofibromas, ungual fibromas and shagreen patch were the second most common major features reported in the literature. However, skin manifestations were not a common led to investigation and diagnosis of TSC. Renal features, mainly angiomyolipomas (AMLs), were the third most common major feature reported. Medical imaging plays an essential role in diagnosis of TSC, and clinical features are important clues that lead to investigation for the disease.

Keywords:  Tuberous sclerosis complex (TSC); cardiac rhabdomyomas; clinical diagnostic criteria; major features; minor features; renal angiomyolipomas (AMLs); subependymal nodules (SENs)

DOI:  https://doi.org/10.21037/qims-21-412
Eur J Pediatr. 2022 Jan 06.

Blood pressure and glomerular filtration rate in youth with tuberous sclerosis complex.

Efthymia Vargiami, Stella Stabouli, Christina Sidira, Maria Kyriazi, Athanasia Anastasiou, Athanasios Notopoulos, Dimitrios Zafeiriou.

  Renal involvement is very common in tuberous sclerosis complex (TSC) and is characterized by the development of angiomyolipoma and cysts. The aims of the present study were to assess kidney function and clinical features of renal involvement in TSC, including kidney function and blood pressure (BP) levels in children, adolescents and young adults. Non-selected patients with a definite diagnosis of TSC attending the paediatric neurology outpatient department of a tertiary hospital were included in a cross-sectional study. All participants had a renal imaging study within 6 months of ambulatory blood pressure (BP) and glomerular filtration rate (GFR) assessment. Data on demographics, history, genotype, kidney function at diagnosis and last imaging were collected. Twenty patients were enrolled in this study with a median age of 15 years (IQR range 9 to 18). About 23.5% of the participants had ambulatory hypertension. Systolic BP levels correlated significantly with GFRDTPA values despite the absence of hyperfiltration. Patients that developed hypertension and possibly those with angiomyolipoma or cysts had higher GFR levels in childhood and adolescence. All the patients with ambulatory hypertension had angiomyolipoma or cysts on renal imaging studies.Conclusions: Hypertension may present with increased frequency in young patients with kidney disease associated with TSC. Routine ambulatory BP measurement should be part of the annual clinical assessment in patients with TSC. What is Known: • Nearly half of the patients with TSC have a premature decline in their renal function in their fifth decade of life. • Hypertension and hyperfiltration have been proposed as modifiable factors of progression of renal decline in patients with TSC-related renal disease. What is New: • Hypertension is prevalent in youth with tuberous sclerosis complex. • SBP levels have a positive relation with GFR levels within the normal range of GFRDTPA values.

Keywords:  Ambulatory blood pressure monitoring; Glomerular filtration rate; Hypertension; Renal angiomyolipoma; Tuberous sclerosis complex

DOI:  https://doi.org/10.1007/s00431-021-04333-3
Cureus. 2021 Nov;13(11): e19900

Rhabdomyoma and Hypoplastic Left Heart Syndrome - Case Report of a Very Rare Combination.

Rahaf Waggass, Hanan S Bin Yahib, Hosam H Bin Seddeq, Aiman Shawli.

  The most benign cardiac tumor in the pediatric population is cardiac rhabdomyoma. They are known to be associated with tuberous sclerosis complex. Here we report a case with multiple cardiac rhabdomyomas and another rare anomaly of the heart known as hypoplastic left heart syndrome. The fetus was antenatally diagnosed with echocardiography which showed both rhabdomyoma and hypoplastic left heart. The patient was started on prostaglandin immediately after birth. He was confirmed postnatally to have inoperable congenital hypoplastic left heart syndrome. On the third day, the baby started to have progressive bradycardia and then died.

Keywords:  cardiac rhabdomyomas; congenital heart disease; echocardiography; hypoplastic left heart syndrome; tuberous sclerosis complex

DOI:  https://doi.org/10.7759/cureus.19900
Cureus. 2021 Dec;13(12): e20131

Hyponatremia: A Tip of the Iceberg in the Late Diagnosis of Tuberous Sclerosis Associated With Lymphangioleiomyomatosis.

David Paiva, Anabela De Carvalho, Ana Luísa Campos, Filipa Gonçalves, Cristina Silva, Olinda Miranda, Sandra Barbosa, Jorge Cotter.

  Tuberous sclerosis (TS) is a rare, autosomal dominant, multisystem genetic disease that causes multiple benign tumors in the brain and other vital organs. Rarely, it can be associated with lymphangioleiomyomatosis (LMA) that is characterized by the proliferation of immature smooth muscle cells in the walls of the airways, venules, and lymphatic vessels in the lung. Here, we present the case of a 44-year-old intellectually disabled woman with a history of marked polydipsia who presented to the emergency department with persistent vomiting. She was hemodynamically stable and did not have any fever. The analytical study showed severe and symptomatic hyponatremia. On physical examination, multiple skin lesions compatible with angiofibromas were noted and the diagnosis of TS was made (confirmed with the genetic study). The multiorgan study documented the presence of multiple cystic images in the lung parenchyma associated with LMA. The aim of this case report is to highlight the importance of targeting cutaneous lesions for a rapid diagnosis of this pathology and to identify the etiology of a severe (symptomatic) ionic disorder and referral to a multidisciplinary team.

Keywords:  angiomyolipomas; hyponatremia; lymphangioleiomyomatosis; polydipsia; tuberous sclerosis

DOI:  https://doi.org/10.7759/cureus.20131
Autophagy. 2022 Jan 05. 1-16

Restoration of mitophagy ameliorates cardiomyopathy in Barth syndrome.

Jun Zhang, Xueling Liu, Jia Nie, Yuguang Shi.

  Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the TAFAZZIN/Taz gene which encodes a transacylase required for cardiolipin remodeling. Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining mitochondrial membrane structure, respiration, mtDNA biogenesis, and mitophagy. Mutations in the TAFAZZIN gene deplete mature cardiolipin, leading to mitochondrial dysfunction, dilated cardiomyopathy, and premature death in BTHS patients. Currently, there is no effective treatment for this debilitating condition. In this study, we showed that TAFAZZIN deficiency caused hyperactivation of MTORC1 signaling and defective mitophagy, leading to accumulation of autophagic vacuoles and dysfunctional mitochondria in the heart of Tafazzin knockdown mice, a rodent model of BTHS. Consequently, treatment of TAFAZZIN knockdown mice with rapamycin, a potent inhibitor of MTORC1, not only restored mitophagy, but also mitigated mitochondrial dysfunction and dilated cardiomyopathy. Taken together, these findings identify MTORC1 as a novel therapeutic target for BTHS, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for BTHS.Abbreviations: BTHS: Barth syndrome; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CL: cardiolipin; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; KD: knockdown; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LV: left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; OCR: oxygen consumption rate; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB/S6K: ribosomal protein S6 kinase beta; SQSTM1/p62: sequestosome 1; TLCL: tetralinoleoyl cardiolipin; WT: wild-type.

Keywords:  BTHS; MTORC1; TAFAZZIN; cardiolipin; mitophagy; rapamycin

DOI:  https://doi.org/10.1080/15548627.2021.2020979
J Cardiovasc Pharmacol. 2021 Dec 27.

mTOR as the therapeutic target of vascular proliferative diseases: past, present, and future.

Wen-Qian Huang, Yan Zou, Ying Tian, Xiao-Feng Ma, Qin-Yi Zhou, Zhen-Yu Li, Shao-Xin Gong, Ai-Ping Wang.

ABSTRACT: The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key pathological characteristic of vascular proliferative diseases. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays an important role in regulating cell growth, motility, proliferation, and survival, as well as gene expression in response to hypoxia, growth factors, and nutrients. Increasing evidence shows that mTOR also regulates VSMC proliferation in vascular proliferative diseases and that mTOR inhibitors, such as rapamycin, effectively restrain VSMC proliferation. However, the molecular mechanisms linking mTOR to vascular proliferative diseases remain elusive. In our review, we summarize the key roles of the mTOR and the recent discoveries in vascular proliferative diseases, focusing on the therapeutic potential of mTOR inhibitors to target mTOR signaling pathway for the treatment of vascular proliferative diseases. Herein, we discuss mTOR inhibitors as promising candidates to prevent VSMC-associated vascular proliferative diseases.

DOI: https://doi.org/10.1097/FJC.0000000000001208
Front Pharmacol. 2021 ;12 801234

mTORC1 Signaling Pathway Mediates Chronic Stress-Induced Synapse Loss in the Hippocampus.

Yu-Fei Luo, Xiao-Xia Ye, Ying-Zhao Fang, Meng-Die Li, Zhi-Xuan Xia, Jian-Min Liu, Xiao-Shan Lin, Zhen Huang, Xiao-Qian Zhu, Jun-Jie Huang, Dong-Lin Tan, Yu-Fei Zhang, Hai-Ping Liu, Jun Zhou, Zu-Cheng Shen.

  Background: The mechanistic target of rapamycin complex 1 (mTORC1) signaling has served as a promising target for therapeutic intervention of major depressive disorder (MDD), but the mTORC1 signaling underlying MDD has not been well elucidated. In the present study, we investigated whether mTORC1 signaling pathway mediates synapse loss induced by chronic stress in the hippocampus. Methods: Chronic restraint stress-induced depression-like behaviors were tested by behavior tests (sucrose preference test, forced swim test and tail suspension test). Synaptic proteins and alternations of phosphorylation levels of mTORC1 signaling-associated molecules were measured using Western blotting. In addition, mRNA changes of immediate early genes (IEGs) and glutamate receptors were measured by RT-PCR. Rapamycin was used to explore the role of mTORC1 signaling in the antidepressant effects of fluoxetine. Results: After successfully establishing the chronic restraint stress paradigm, we observed that the mRNA levels of some IEGs were significantly changed, indicating the activation of neurons and protein synthesis alterations. Then, there was a significant downregulation of glutamate receptors and postsynaptic density protein 95 at protein and mRNA levels. Additionally, synaptic fractionation assay revealed that chronic stress induced synapse loss in the dorsal and ventral hippocampus. Furthermore, these effects were associated with the mTORC1 signaling pathway-mediated protein synthesis, and subsequently the phosphorylation of associated downstream signaling targets was reduced after chronic stress. Finally, we found that intracerebroventricular infusion of rapamycin simulated depression-like behavior and also blocked the antidepressant effects of fluoxetine. Conclusion: Overall, our study suggests that mTORC1 signaling pathway plays a critical role in mediating synapse loss induced by chronic stress, and has part in the behavioral effects of antidepressant treatment.

Keywords:  chronic restraint stress; depression; fluoxetine; mammalian target of rapamycin; postsynaptic density protein 95

DOI:  https://doi.org/10.3389/fphar.2021.801234