bims-tubesc 2023-03-12 papers

Issue of 2023–03–12
six papers selected by

Ann Clin Lab Sci. 2023 Jan;53(1): 3-13

Review: Mammalian Target of Rapamycin (mTOR) Pathway Is Critical in Developing Most Renal Cell Tumors.

Kevin J Zhang, Zhenhong Qu, Elan Pszenica, Jason M Hafron, Ping L Zhang, Robert E Brown.

OBJECTIVE: Various renal cell carcinomas (RCC) are derived from different segments of the renal tubular origin, which determines their morphological and immunohistochemical phenotype and their molecular signaling pathway as a therapeutic target. Most of these tumors utilize the mammalian target of rapamycin (mTOR) pathway to activate pathways involving metabolic and nutritional supplies.
METHODS: Overexpressed mTOR signals are reported in more than 90% of the most common types of RCC. Many new renal tumor entities have been reported in recent years.
RESULTS: Among them, somatic mutations in tuberous sclerosis complex (TSC) result in loss of its normal inhibitory control over mTOR, thus promoting mTOR-associated proliferative activities in several new renal neoplastic entities including RCC with fibromyomatous stroma (RCCFMS), eosinophilic vacuolated tumor, eosinophilic solid & cystic RCC, and low-grade oncocytic tumor.
CONCLUSIONS: This short review provides a comprehensive correlation of tumor morphology and immunohistochemical phenotype with renal tubular differentiation and their shared mTOR. These essential pieces of knowledge are vital in the diagnosis and clinical management of renal cell neoplasms.

Keywords: mTOR; mutations; renal cell neoplasm; treatment resistance; tuberous sclerosis complex

Hum Pathol. 2023 Mar 07. pii: S0046-8177(23)00040-0. [Epub ahead of print]

Reprint of: lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas & renal cell carcinoma.

Sounak Gupta, Melissa L Stanton, Jordan P Reynolds, Rumeal D Whaley, Loren Herrera-Hernandez, Rafael E Jimenez, John C Cheville.

Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.

Keywords: Angiomyolipoma; Renal cell carcinoma; Renal cysts; TSC; TSC1/TSC2; Tuberous sclerosis complex

DOI: https://doi.org/10.1016/j.humpath.2023.02.012

Front Med (Lausanne). 2023 ;10 1101079

TSC2/PKD1 contiguous deletion syndrome in a pregnant woman: A case report.

Shaofang Huang, Kangxiang Xu, Yuqi Xu, Lu Zhao, Xiaoju He.

TSC2/PKD1 contiguous gene deletion syndrome is a disease caused by the deletions of the TSC2 and PKD1 genes. This is a rare contiguous genomic disease with clinical manifestations of tuberous sclerosis and polycystic kidney disease. To our knowledge, this case report is the first known case of TSC2/PKD1 contiguous gene deletions in a pregnant woman. The patient had multiple renal cysts, angiomyolipoma, hypomelanotic macules, shagreen patch, subependymal giant cell astrocytoma, multiple cortical tubers, and subependymal nodules. The patient underwent genetic testing. To exclude genetic defects in the fetus, prenatal fetal genetic testing was performed after obtaining the patient's consent. We found an increasing trend in the size of renal cysts and renal angiomyolipomas in patients with polycystic kidney with tuberous sclerosis during pregnancy. Through enhanced clinical monitoring of patients and prenatal genetic testing of the fetus, timely and effective clinical intervention for the mother may be achieved, thus obtaining the best possible outcome for both mother and fetus.

Keywords: TSC2/PKD1 contiguous gene deletions; polycystic kidney disease; pregnant woman; prenatal diagnosis; renal angiomyolipoma; tuberous sclerosis

DOI: https://doi.org/10.3389/fmed.2023.1101079

CNS Neurosci Ther. 2023 Mar 08.

Inhibition of mammalian target of rapamycin complex 1 in the brain microvascular endothelium ameliorates diabetic Aβ brain deposition and cognitive impairment via the sterol-regulatory element-binding protein 1/lipoprotein receptor-associated protein 1 signaling pathway.

Gege Jiang, Zhenzhen Long, Yaoling Wang, Yaofeng Wang, Ping Xue, Minfang Chen, Kang Yang, Wei Li.

AIMS: Mammalian target of rapamycin complex 1 (mTORC1) is highly activated in diabetes, and the decrease of low-density lipoprotein receptor-associated protein 1 (LRP1) in brain microvascular endothelial cells (BMECs) is a key factor leading to amyloid-β (Aβ) deposition in the brain and diabetic cognitive impairment, but the relationship between them is still unknown.
METHODS: In vitro, BMECs were cultured with high glucose, and the activation of mTORC1 and sterol-regulatory element-binding protein 1 (SREBP1) was observed. mTORC1 was inhibited by rapamycin and small interfering RNA (siRNA) in BMECs. Betulin and siRNA inhibited SREBP1, observed the mechanism of mTORC1-mediated effects on Aβ efflux in BMECs through LRP1 under high-glucose conditions. Constructed cerebrovascular endothelial cell-specific Raptor-knockout (Raptorfl/+ ) mice to investigate the role of mTORC1 in regulating LRP1-mediated Aβ efflux and diabetic cognitive impairment at the tissue level.
RESULTS: mTORC1 activation was observed in HBMECs cultured in high glucose, and this change was confirmed in diabetic mice. Inhibiting mTORC1 corrected the reduction in Aβ efflux under high-glucose stimulation. In addition, high glucose activated the expression of SREBP1, and inhibiting of mTORC1 reduced the activation and expression of SREBP1. After inhibiting the activity of SREBP1, the presentation of LRP1 was improved, and the decrease of Aβ efflux mediated by high glucose was corrected. Raptorfl/+ diabetic mice had significantly inhibited activation of mTORC1 and SREBP1, increased LRP1 expression, increased Aβ efflux, and improved cognitive impairment.
CONCLUSION: Inhibiting mTORC1 in the brain microvascular endothelium ameliorates diabetic Aβ brain deposition and cognitive impairment via the SREBP1/LRP1 signaling pathway, suggesting that mTORC1 may be a potential target for the treatment of diabetic cognitive impairment.

Keywords: amyloid-β; brain microvascular endothelial cells; cognitive impairment; diabetes; mTORC1

DOI: https://doi.org/10.1111/cns.14133

J Nutr. 2023 Mar 02. pii: S0022-3166(23)35277-5. [Epub ahead of print]

Modifying dietary protein impacts mTOR signaling and brain deposition of amyloid beta in a knock-in mouse model of Alzheimer's disease.

Julien Bensalem, Leanne K Hein, Sofia Hassiotis, Paul J Trim, Christopher G Proud, Leonie K Heilbronn, Timothy J Sargeant.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition defined by the build-up of amyloid plaques in the brain and intraneuronal tangles of the protein tau. Autophagy is a cellular cleaning process involved in the degradation of proteins, including proteins directly responsible for amyloid plaques, but its activity is compromised in AD. The mechanistic target of rapamycin complex 1 (mTORC1) inhibits autophagy when activated by amino acids.
OBJECTIVES: We therefore hypothesized that reducing amino acid intake by decreasing dietary protein could promote autophagy which in turn could prevent amyloid plaque deposition in mice.
METHODS: Homozygote (2-month old) and heterozygote (4-month old) amyloid precursor protein (APP) NL-G-F mice, a model of brain amyloid deposition, were used in this study to test this hypothesis. Male and female mice were fed one of three isocaloric low-protein, control, or high-protein diets for four months and then humanely killed for analysis. Locomotor performance was measured using the inverted screen test and body composition was measured using EchoMRI. Samples were analyzed using western blotting, enzyme-linked immunosorbent assay (ELISA), mass spectrometry, and immunohistochemical staining.
RESULTS: mTORC1 activity in the cerebral cortex was inversely co-varied with protein consumption in both homozygote and heterozygote mice. Low-protein diet improved metabolic parameters and restored locomotor performance only in male homozygous mice. Dietary protein adjustment did not impact amyloid deposition in homozygous mice. However, in the heterozygous APP NL-G-F mice, amyloid plaque was lower in male mice consuming the low-protein compared with control diet.
CONCLUSIONS: Thus, reducing protein intake reduces mTORC1 activity and may prevent amyloid accumulation, at least in male mice. This study shows that dietary protein is a tool that can be used to change mTORC1 activity and amyloid deposition in the mouse brain and also demonstrates that the murine brain's response to dietary protein is sex specific.

Keywords: Alzheimer’s disease; autophagy; diet; mTOR; macronutrient

DOI: https://doi.org/10.1016/j.tjnut.2023.02.035

Aging (Albany NY). 2023 Feb 24. 15(4): 1039-1051

RIOK3 promotes mTORC1 activation by facilitating SLC7A2-mediated arginine uptake in pancreatic ductal adenocarcinoma.

Henan Qin, Rui Sun, Xin Guo, Lei Fang, Mengyuan Xu, Yibin Teng, Ning Zhen, Aman Wang, Jiwei Liu.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis. Reprogramming of amino acid metabolism is one of the characteristics of PDAC, in which arginine metabolism is significantly altered in PDAC cells and is involved in important signaling pathways. Current studies have identified arginine deprivation as a potential strategy for PDAC treatment. In this study, we performed Liquid Chromatograph Mass Spectrometer (LC-MS)-based non-targeted metabolomic analysis on PDAC cell lines with stable Rio Kinase 3 (RIOK3) knockdown and PDAC tissues with different RIOK3 expressions and found that RIOK3 expression was significantly correlated with arginine metabolism in PDAC. Subsequent RNA sequencing (RNA-Seq) and Western blot analysis showed that RIOK3 knockdown significantly inhibited the expression of arginine transporter solute carrier family 7 member 2 (SLC7A2). Further studies revealed that RIOK3 promoted arginine uptake, mechanistic target of rapamycin complex 1 (mTORC1) activation, cell invasion, and metastasis in PDAC cells via SLC7A2. Finally, we found that patients with high expression of both RIOK3 and infiltrating Treg cells had a worse prognosis. Overall, our study found that RIOK3 in PDAC cells promotes arginine uptake and mTORC1 activation through upregulation of SLC7A2 expression, and also provides a new therapeutic target for therapeutic strategies targeting arginine metabolism.

Keywords: RIOK3; SLC7A2; Treg; arginine metabolism; pancreatic ductal adenocarcinoma

DOI: https://doi.org/10.18632/aging.204528