FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland

Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.

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B cells promote hepatic inflammation, biliary cyst formation, and salivary gland inflammation in the NOD.c3c4 model of autoimmune cholangitis

Cellular Immunology ◽

10.1016/j.cellimm.2011.01.005 ◽

2011 ◽

Vol 268 (1) ◽

pp. 16-23 ◽

Cited By ~ 16

Author(s):

Yuki Moritoki ◽

Masanobu Tsuda ◽

Koichi Tsuneyama ◽

Weici Zhang ◽

Katsunori Yoshida ◽

...

Keyword(s):

Salivary Gland ◽

B Cells ◽

Cyst Formation ◽

Autoimmune Cholangitis ◽

Hepatic Inflammation ◽

Biliary Cyst

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Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming

10.1101/393876 ◽

2018 ◽

Cited By ~ 1

Author(s):

Raquel Buj ◽

Chi-Wei Chen ◽

Erika S. Dahl ◽

Kelly E. Leon ◽

Ross Kuskovsky ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

List Type ◽

Multiple Cancer ◽

Nucleotide Synthesis ◽

Mtorc1 Signaling

SummaryReprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurred via activation of mTORC1 signaling, which directly mediated increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlated with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibited proliferation only in p16-low cells by inducing senescence bothin vitroandin vivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells.HighlightsmTORC1 is activated by p16 knockdown to increase nucleotide synthesis and bypass senescencemTORC1 directly increases translation RPIA to increase ribose-5-phosphateActivation of mTORC1 pathway downstream of p16 suppression is independent of RBRPIA suppression induces senescence only in cells and tumors with low p16

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Salivary gland anlage tumor. A case with widespread necrosis and large cyst formation

Pathology ◽

10.1080/00313029600169723 ◽

1996 ◽

Vol 28 (2) ◽

pp. 128-130 ◽

Cited By ~ 15

Author(s):

Michal Michal ◽

Ladislav Sokol ◽

Petr Mukenšnabl

Keyword(s):

Salivary Gland ◽

Cyst Formation ◽

Large Cyst

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Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050755 ◽

1974 ◽

Vol 32 ◽

pp. 148-149

Author(s):

D. E. Philpott ◽

A. Takahashi

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Salivary Gland ◽

Carotid Artery ◽

Basement Membrane ◽

Coronary Vessels ◽

Ruthenium Red ◽

E Coli ◽

Old Rats ◽

The Brain

Two month, eight month and two year old rats were treated with 10 or 20 mg/kg of E. Coli endotoxin I. P. The eight month old rats proved most resistant to the endotoxin. During fixation the aorta, carotid artery, basil arartery of the brain, coronary vessels of the heart, inner surfaces of the heart chambers, heart and skeletal muscle, lung, liver, kidney, spleen, brain, retina, trachae, intestine, salivary gland, adrenal gland and gingiva were treated with ruthenium red or alcian blue to preserve the mucopolysaccharide (MPS) coating. Five, 8 and 24 hrs of endotoxin treatment produced increasingly marked capillary damage, disappearance of the MPS coating, edema, destruction of endothelial cells and damage to the basement membrane in the liver, kidney and lung.

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Electron Beam-Induced Mass Loss in Freeze-Dried Tissue and Protein Samples

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011917x ◽

1985 ◽

Vol 43 ◽

pp. 470-471

Author(s):

M.E. Cantino ◽

M.K. Goddard ◽

L.E. Wilkinson ◽

D.E. Johnson

Keyword(s):

Electron Beam ◽

Salivary Gland ◽

Mass Loss ◽

Counting Rate ◽

Dose Dependence ◽

X Ray ◽

Large Samples ◽

Freeze Dried ◽

Muscle Homogenate ◽

Large Muscle

Quantification in biological x-ray microanalysis depends on accurate evaluation of mass loss. Although several studies have addressed the problem of electron beam induced mass loss from organic samples (eg., 1,2). uncertainty persists as to the dose dependence, the extent of loss, the elemental constituents affected, and the variation in loss for different materials and tissues. in the work described here, we used x-ray counting rate changes to measure mass loss in albumin (used as a quantification standard), salivary gland, and muscle.In order to measure mass loss at low doses (10-4 coul/cm2 ) large samples were needed. While freeze-dried salivary gland sections of the required dimensions were available, muscle sections of this size were difficult to obtain. To simulate large muscle sections, frog or rat muscle homogenate was injected between formvar films which were then stretched over slot grids and freeze-dried. Albumin samples were prepared by a similar procedure. using a solution of bovine serum albumin in water. Samples were irradiated in the STEM mode of a JEOL 100C.

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