c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism

By Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Kayoko Kita, T. Ochi, Karen I. Zeller, A. D. De Marzo, J. V. Van Eyk, Joshua T. Mendell and 1 more. Nature, 2009

1,166 citations recorded by the source corpus.

Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c4835b3c8f40ea13f5264480a94fa62fbbee937b

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Citations in the corpus

Regulation of cancer cell metabolism (2011, background): “However, it has recently been shown that transformation stimulates glutaminolysis and that many tumour cells are critically dependent on this amino aci”
Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, positive): “Glutamine uptake and metabolism is regulated by the oncogene MYC, and MYCtransformed cells become addicted to glutamine through increased expression of glutamine transporters and glutamine catabolic enzymes (Dang 2010, Gao et al 2009, Wise et al 2008).”
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation (2011, background): “Recent studies in human cell lines have suggested that enforced expression of Myc regulates the rate-limiting glutaminolyic enzyme glutaminase 1 (Gls1) through both transcription and posttranscriptional mechanisms (Gao et al., 2009; Wise et al., 2008), and p53 regulates the transcription of glutamin”
Glutaminolysis activates Rag-mTORC1 signaling. (2012, background): “GLS is regulated at the expression level by the oncogene c-myc (Gao et al., 2009; Wise et al., 2008), and GLS activity correlates with tumor growth (Pérez-Gómez et al., 2005; Tennant et al., lecular Cell 47, 349–358, August 10, 2012 ª2012 Elsevier Inc. 349 A B - + LQ…”
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer (2014, background): “A critical step in the utilization of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (5, 6).”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Whereas Myc specifically potentiates elevated expression of GLS1 and promotes the downstream utilization of glutamine carbon in anaplerosis (55, 56), p53 specifically activates GLS2 to support cellular defense against oxidative stress (130).”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “, and MYC -dependent cells have a particular reliance on glutamine metabolis”
The microcosmos of cancer (2012, background): “The enhanced glutaminolysis observed in cancer cells can be partially explained by MYC-mediated repression of miR-23a and miR-23b (ref”
MYC on the Path to Cancer (2012, background): “In addition, Myc regulates energy metabolism through its direct activation of genes involved in glycolysis, glutamine metabolism, and mitochondrial biogenesis (Gao et al., 2009; Li et al., 2005; Osthus et al., 2000; Shim et al., 1997; Wise et al., 2008).”
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia (2011, background): “, which in turn drives glutamine catabolism through the regulation of numerous genes including glutaminas”
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity (2010, background): “Glutamate, the product of GLS, is also required for generation of glutathione and NAPDH to provide redox balance (15).”
Metabolic Regulation of T Lymphocytes (2013, background): “Specifically, c-Myc can direct the expression of all the glycolytic genes, including Glut1, lactate dehydrogenase A (LDHA), PKM2, and hexokinase 2 (31), as well as glutaminase and the glutamine transporters SLC3a2, SLC5A1, and SLC7A1 (32, 33).”
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Glutamine Addiction: A New Therapeutic Target in Cancer (2010, background): “[41] found that glutaminase protein levels were significantly upregulated in Myc-overexpressing Wise and Thompson Page 4”
PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress (2013, neutral): “For example, tumor cells are able to generate ATP through mitochondrial oxidation of fatty acids and amino acids, such as glutamine when glucose becomes limiting (Zaugg et al., 2011; Choo et al., 2010; Gao et al., 2009; Wise et al., 2008).”