4 results on '"Nada Y. Kalaany"'
Search Results
2. Starved epithelial cells uptake extracellular matrix for survival
- Author
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Taru Muranen, Marcin P. Iwanicki, Natasha L. Curry, Julie Hwang, Cory D. DuBois, Jonathan L. Coloff, Daniel S. Hitchcock, Clary B. Clish, Joan S. Brugge, and Nada Y. Kalaany
- Subjects
Science - Abstract
Inhibition of PI3K/mTOR, which mimics nutrient starvation, causes death of detached but not matrix-attached cancer cells. Here the authors show that nutrient restriction of epithelial cells causes uptake of the matrix protein laminin, which results in increased intracellular amino acids and enhanced mTORC1 signalling.
- Published
- 2017
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3. Critical role for arginase 2 in obesity-associated pancreatic cancer
- Author
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Lin Lin, Tamara Zaytouni, Patrick J Lenehan, Eduardo M. Torres, Daniel S. Hitchcock, Mari Mino-Kenudson, Nada Y. Kalaany, Cory D. Dubois, Vicente Morales-Oyarvide, Nicholas Stylopoulos, Elizaveta Freinkman, Brian M. Wolpin, Pei-Yun Tsai, and Clary B. Clish
- Subjects
0301 basic medicine ,Male ,Ornithine ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Arginine ,health care facilities, manpower, and services ,Science ,education ,General Physics and Astronomy ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Mucoproteins ,Internal medicine ,Pancreatic cancer ,health services administration ,medicine ,Animals ,Humans ,Obesity ,ARG1 ,ARG2 ,2. Zero hunger ,Mice, Knockout ,Oncogene Proteins ,Multidisciplinary ,Proteins ,General Chemistry ,Metabolism ,medicine.disease ,3. Good health ,Mitochondria ,Arginase ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Endocrinology ,chemistry ,Urea cycle ,Carcinoma, Pancreatic Ductal - Abstract
Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer., Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.
- Published
- 2017
4. Starved epithelial cells uptake extracellular matrix for survival
- Author
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Julie Hwang, Jonathan L. Coloff, Nada Y. Kalaany, Clary B. Clish, Natasha L. Curry, Joan S. Brugge, Taru A. Muranen, Marcin P. Iwanicki, Cory D. Dubois, and Daniel S. Hitchcock
- Subjects
0301 basic medicine ,Programmed cell death ,Cell Survival ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Physiology ,Mice, Inbred Strains ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Extracellular matrix ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Laminin ,medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,2. Zero hunger ,Multidisciplinary ,biology ,Chemistry ,Growth factor ,Integrin beta4 ,Epithelial Cells ,General Chemistry ,Fibroblasts ,Extracellular Matrix ,Cell biology ,030104 developmental biology ,Adipose Tissue ,Starvation ,Cell culture ,Cancer cell ,biology.protein ,Female - Abstract
Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell β4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition., Inhibition of PI3K/mTOR, which mimics nutrient starvation, causes death of detached but not matrix-attached cancer cells. Here the authors show that nutrient restriction of epithelial cells causes uptake of the matrix protein laminin, which results in increased intracellular amino acids and enhanced mTORC1 signalling.
- Published
- 2017
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