Role of Glutamine in Cancer: Therapeutic and Imaging Implications: FIGURE 1.

Rajagopalan, Kartik N.; DeBerardinis, Ralph J.

doi:10.2967/jnumed.110.084244

Cited by 103 publications

(86 citation statements)

References 29 publications

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“…It is an alternative energy source and a constant source of carbon and nitrogen building blocks for production of new cells (15,16). It may also be possible that glutamine's role in the cell may not be limited to serving as an anabolic substrate.…”

Section: Discussionmentioning

confidence: 99%

“…These processes may not be mutually exclusive and therefore, this may be a clever and essential strategy adopted by tumor cells for survival (2,(8)(9)(10)(11). Recently, a series of papers suggests that 18 F-FDG-negative tumors may use a different metabolic pathway-glutaminolysis (7,(12)(13)(14)(15)(16). The results, at least partially, provide a probable explanation for the observation that 18 F-FDG PET fails to spot certain tumors in cancer patients.…”

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confidence: 99%

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PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

Lieberman

Plöessl²,

Wang³

et al. 2011

J Nucl Med

157

183

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Changes in gene expression, metabolism, and energy requirements are hallmarks of cancer growth and self-sufficiency. Upregulation of the PI3K/Akt/mTor pathway in tumor cells has been shown to stimulate aerobic glycolysis, which has enabled 18 F-FDG PET tumor imaging. However, of the millions of 18 F-FDG PET scans conducted per year, a significant number of malignant tumors are 18 F-FDG PET-negative. Recent studies suggest that several tumors may use glutamine as the key nutrient for survival. As an alternative metabolic tracer for tumors, 18 F-(2S,4R)4-fluoroglutamine was developed as a PET tracer for mapping glutaminolytic tumors. Methods: A series of in vitro cell uptake and in vivo animal studies were performed to demonstrate tumor cell addiction to glutamine. Cell uptake studies of this tracer were performed in SF188 and 9L glioblastoma tumor cells. Dynamic small-animal PET studies of 18 F-(2S,4R)4-fluoroglutamine were conducted in 2 animal models: xenografts produced in F344 rats by subcutaneous injection of 9L tumor cells and transgenic mice with M/tomND spontaneous mammary gland tumors. Results: In vitro studies showed that both transformed 9L and SF188 tumor cells displayed a high rate of glutamine uptake (maximum uptake, 16% dose/100 mg of protein). The cell uptake of 18 F-(2S,4R)4-fluoroglutamine by SF188 cells is comparable to that of 3 H-L-glutamine but higher than that of 18 F-FDG. The tumor cell uptake can be selectively blocked. Biodistribution and PET studies showed that 18 F-(2S,4R)4-fluoroglutamine localized in tumors with a higher uptake than in surrounding muscle and liver tissues. Data suggest that certain tumor cells may use glutamine for energy production. Conclusion: The results support that 18 F-(2S,4R)4-fluoroglutamine is selectively taken up and trapped by tumor cells. It may be useful as a novel metabolic tracer for tumor imaging.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

Lieberman

Plöessl²,

Wang³

et al. 2011

J Nucl Med

157

183

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“…The levels of glutamine are elevated in multiple cancers, which are indispensable for cancer growth and survival [49]. Particularly, in certain cancer cells, glutamine tends to replace glucose for playing a role in carbon source through glutaminolysis.…”

Section: Autophagy In Glutamine Metabolismmentioning

confidence: 99%

Role of Autophagy in Cancer Metabolism

Cheong¹

2016

Autophagy in Current Trends in Cellular Physiology and Pathology

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Cancer cells undergo a wide range of metabolic reprogramming to take advantage for supporting rapid growth and survival. Autophagy plays a critical role in directly regulating cellular metabolism as a main catabolic process mediated by lysosomal degradation in response to the metabolic stress. During cancer development, autophagy plays opposite functions in suppressing or promoting tumors dependent of distinct stage. Autophagy maintains cellular homeostasis by degrading unnecessary cellular molecules and oncogenic products, thereby suppressing tumorigenesis. By contrast, autophagy enables to promote cancer growth in advanced tumor by supplying nutrients and relieving metabolic stress.In this book chapter, recent progress indicates how autophagy is integrated with cellular metabolic alteration during cancer development, particularly focusing on distinct metabolic substrates including glucose or glutamine. Multiple mechanisms would be suggested to explain the functions of autophagy at distinct stage of tumor progression. Cancer metabolic alterations associated with autophagy can be determined by certain oncogenic activators and/or tumor suppressors. Understanding the molecular mechanism of autophagy and metabolic alteration during cancer development may suggest potential targets for therapeutic intervention.

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“…Furthermore, oncogenes such as MYC, NF-kB, AKT, tyrosine kinases and tumour suppressor genes including TP53 and PTEN that have been linked to increased glycolysis, have also been implicated in the upregulation of glutamine [28]. Glutamine function as a source of both nitrogen and carbon and contains amino and amido nitrogens, which are transferred to metabolic intermediates in the synthesis of nucleic acids, proteins, and hexosamines making it a crucial nutrient during cell proliferation [29,30]. It is not surprising that novel imaging strategies focusing on glutamine that could provide a valuable complement to 18 F-FDG PET, because glutamine complements glucose in the metabolic platforms that support tumour growth at the cellular level [29].…”

Section: Furthermore It Has Been Shown That O-glcnac Modification Ofmentioning

confidence: 99%

“…Glutamine function as a source of both nitrogen and carbon and contains amino and amido nitrogens, which are transferred to metabolic intermediates in the synthesis of nucleic acids, proteins, and hexosamines making it a crucial nutrient during cell proliferation [29,30]. It is not surprising that novel imaging strategies focusing on glutamine that could provide a valuable complement to 18 F-FDG PET, because glutamine complements glucose in the metabolic platforms that support tumour growth at the cellular level [29]. It should be noted that hexosamine biosynthesis integrates glucose and glutamine metabolism because the rate limiting step is the addition of the ã-amido group of glutamine to a hexose sugar by the enzyme glutamine fructose-6-phosphate amidotransferase [8].…”

Section: Furthermore It Has Been Shown That O-glcnac Modification Ofmentioning

confidence: 99%

Reprogrammed Cellular Metabolism and O -GlcNAc Modification in Cancer

Mishra¹

2012

Transl Med

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The capability to reprogram cellular metabolism in order to most effectively support proliferating cancer cells has been emerging as a hallmark of cancer. As a result, there has been a resurgence of interest in the field of tumour metabolism. Additionally, this reappearance in interest may partly be attributed to the tremendous capability of the recent technological advancement to explore the relationship between cellular metabolism and cancer to an extent which was not possible before. The most fundamental trait of cancer cells involves their ability to sustain cell proliferation in an uncontrolled manner. Uncontrolled cell growth also require intracellular metabolic adjustment to meet the continual demand of energy and macromolecules by the proliferating cells [1]. This necessity is well known to be served by increased glucose uptake and anaerobic glycolysis by cancer cells, also known as the Warburg effect [2]. This shift in tumour metabolism is critical for supporting cancer cells as increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids. This, in turn, facilitates the biosynthesis of the macromolecules and organelles required for assembling new cells [3]. Moreover, the Warburg-like metabolism seems to be present in many rapidly dividing embryonic tissues, once again suggesting a role in supporting the large-scale biosynthetic programs that are required for active cell proliferation [1,4]. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumour microenvironment, oncogenic signaling, and an abnormal expression of metabolic enzymes [5]. However, it is not known that such shift in metabolism also payback to cancer promoting proteins in a way which further facilitates their function or prevents their downregulation, thereby constituting a vicious circle in favour of cancer cells. One such potential mechanism may involve the hexosamine biosynthetic pathway (HBP) and the post-translational modification of protein by b-N-acetylglcosamine (O-GlcNAc); as changes in glucose uptake and metabolism also alter nutrient signaling pathways, including HBP [6,7]. The final product of HBP is uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) [8]. The UDPGlcNAc is a donor substrate for the post-translational modification at serine and threonine residues of a wide range of proteins including proteins known to be involved in the pathogenesis and progression of cancer (e.g. proteins enhancing glucose uptake, tumour suppressors, oncogenes, metabolic enzymes and mitochondrial proteins) [9]. For example, the constitutive activation of phosphatidylinositol 3 kinase/ protein kinase B (PI3K/Akt) pathway is known to upregulates glucose uptake in cancer cells, and various components involved in this process are known to undergo O-GlcNAc modification [9,10]...

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Role of Glutamine in Cancer: Therapeutic and Imaging Implications: FIGURE 1.

Cited by 103 publications

References 29 publications

PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

Role of Autophagy in Cancer Metabolism

Reprogrammed Cellular Metabolism and O -GlcNAc Modification in Cancer

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Role of Glutamine in Cancer: Therapeutic and Imaging Implications: FIGURE 1.

Cited by 103 publications

References 29 publications

PET Imaging of Glutaminolysis in Tumors by 18F-(2S,4R)4-Fluoroglutamine

PET Imaging of Glutaminolysis in Tumors by 18F-(2S,4R)4-Fluoroglutamine

Role of Autophagy in Cancer Metabolism

Reprogrammed Cellular Metabolism and O -GlcNAc Modification in Cancer

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Product

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PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine