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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Cosimo Commisso,Shawn M. Davidson,Rengin G. Soydaner-Azeloglu,Seth J. Parker,Jurre J. Kamphorst,Sean R. Hackett,Elda Grabocka,Michel Nofal,Jeffrey A. Drebin,Craig B. Thompson,Joshua D. Rabinowitz,Christian M. Metallo,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Dafna Bar-Sagi +14 more
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TLDR
It is shown that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell, and its pharmacological inhibition compromises the growth of Ras- transformed pancreatic tumour xenografts.Abstract:
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.read more
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References
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Journal Article
ras Oncogenes in Human Cancer: A Review
TL;DR: It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly and some evidence that environmental agents may be involved in the induction of the mutations.
Journal ArticleDOI
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Siân Jones,Xiaosong Zhang,D. Williams Parsons,D. Williams Parsons,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,Hirohiko Kamiyama,Antonio Jimeno,Seung-Mo Hong,Baojin Fu,Ming Tseh Lin,Eric S. Calhoun,Mihoko Kamiyama,Kimberly Walter,Tatiana Nikolskaya,Yuri Nikolsky,James Hartigan,Douglas Smith,Manuel Hidalgo,Steven D. Leach,Alison P. Klein,Elizabeth M. Jaffee,Michael Goggins,Anirban Maitra,Anirban Maitra,Christine A. Iacobuzio-Donahue,James R. Eshleman,Scott E. Kern,Ralph H. Hruban,Rachel Karchin,Nickolas Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +37 more
TL;DR: It is found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations, which defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors.
Journal ArticleDOI
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Sunil R. Hingorani,Lifu Wang,Asha S. Multani,Chelsea Combs,Therese B. Deramaudt,Ralph H. Hruban,Anil K. Rustgi,Sandy Chang,David A. Tuveson +8 more
TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
Journal ArticleDOI
Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction
David R. Wise,Ralph J. DeBerardinis,Anthony A. Mancuso,Nabil Sayed,Xiao-yong Zhang,Harla K. Pfeiffer,Ilana Nissim,Evgueni Daikhin,Marc Yudkoff,Steven B. McMahon,Craig B. Thompson +10 more
TL;DR: It is reported that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis, resulting in the reprogramming of mitochondrial metabolism to depend on glutaminolysis to sustain cellular viability and TCA cycle anapleurosis.
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Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Christian M. Metallo,Paulo A. Gameiro,Eric L. Bell,Katherine R. Mattaini,Juanjuan Yang,Karsten Hiller,Karsten Hiller,Christopher M. Jewell,Zachary R. Johnson,Darrell J. Irvine,Darrell J. Irvine,Leonard Guarente,Joanne K. Kelleher,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Othon Iliopoulos,Gregory Stephanopoulos +16 more
TL;DR: It is shown that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis and support lipid synthesis in mammalian cells.