bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021‒06‒13
seven papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Adv Sci (Weinh). 2021 06;8(11): e2003732
      Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1-mediated down-regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.
    Keywords:  COQ9; COX4; DDIT3/CHOP; electron transfer chain; glutamine deprivation; glycolysis
  2. Cell Metab. 2021 May 31. pii: S1550-4131(21)00226-6. [Epub ahead of print]
      Mechanical signals from the tumor microenvironment modulate cell mechanics and influence cell metabolism to promote cancer aggressiveness. Cells withstand external forces by adjusting the stiffness of their cytoskeleton. Microtubules (MTs) act as compression-bearing elements. Yet how cancer cells regulate MT dynamic in response to the locally constrained environment has remained unclear. Using breast cancer as a model of a disease in which mechanical signaling promotes disease progression, we show that matrix stiffening rewires glutamine metabolism to promote MT glutamylation and force MT stabilization, thereby promoting cell invasion. Pharmacologic inhibition of glutamine metabolism decreased MT glutamylation and affected their mechanical stabilization. Similarly, decreased MT glutamylation by overexpressing tubulin mutants lacking glutamylation site(s) decreased MT stability, thereby hampering cancer aggressiveness in vitro and in vivo. Together, our results decipher part of the enigmatic tubulin code that coordinates the fine-tunable properties of MT and link cell metabolism to MT dynamics and cancer aggressiveness.
    Keywords:  breast cancer; cancer cell metabolism; glutamine metabolism; glutamylation; mechanobiology; microtubules; posttranslational modifications
  3. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Feb 25. 50(1): 32-40
      The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.
    Keywords:  Cell metabolism; Drug resistance; Glutamine; Review; Tumor
  4. Cancer Sci. 2021 Jun 06.
      Amino acids are indispensable nutrients for both normal and cancer cells. Cancer cells are unable to synthesize essential amino acids as well as some non-essential amino acids adequately to support rapid proliferation, and must uptake amino acids from the surroundings. In order to meet the increased demand for amino acids needed for proliferation, high levels of amino acid transporters are expressed on the surface of cancer cells. Cancer cells utilize amino acids to synthesize proteins and nucleotides, as well as to obtain energy. In addition, amino acids are known to play pathological roles in cancer cells. Interestingly, breast cancer cells limit the use of amino acids for cell proliferation according to amino acid availability, which depends on estrogen receptor status. Here, we present a summarized literature review of novel amino acid functions in cancer cells. This review organizes the knowledge available on two amino acid transporters, SLC7A5 and SLC7A11, which are considered essential for breast cancer cell growth in a cell-dependent manner. In particular, we propose the glutamine recycling model to clarify the mechanism underlying aberrant SLC7A5 activation. Finally, we overview the pathological significances of SLC7A5 and SLC7A11 in cancer tissues.
    Keywords:  Amino acid transporter; Breast cancer; Cell proliferation; Cystine uptake; Leucine uptake
  5. J Agric Food Chem. 2021 Jun 07.
      In the dairy industry, glutamine (Gln) is often used as a feed additive to increase milk yield and quality; however, the molecular regulation underneath needs further clarification. Here, with bovine mammary epithelial cells (BMECs), the effects and mechanisms of Gln on cell growth and casein synthesis were assessed. When Gln was added or depleted from BMECs, both cell growth and β-casein (CSN2) expression were increased or decreased, respectively. Overexpressing or inhibiting the mechanistic target of rapamycin (mTOR) revealed that Gln regulated cell growth and CSN2 synthesis through the mTORC1 pathway. A similar intervention of ADP-ribosylation factor 1 (Arf1) uncovered that Gln activated the mTORC1 pathway through Arf1. We next observed that both guanine nucleotide exchange factors, Cytohesin-1/2/3 (CYTH1/2/3, CYTHs) and ADP-ribosylation factor GTPase activating protein 1 (ARFGAP1), interacted with Arf1. Inhibiting CYTHs or ARFGAP1 showed that Gln supplement or depletion activated or inactivated Arf1 through CYTHs or ARFGAP1, respectively. Collectively, this study demonstrated that Gln positively regulated cell growth and casein synthesis in BMECs, which works through the CYTHs/ARFGAP1-Arf1-mTORC1 pathway. These results greatly enhanced current understanding regarding the regulation of the mTOR pathway and provided new insights for the processes of cell growth and casein synthesis by amino acids, particularly Gln.
    Keywords:  ADP-ribosylation factor 1; ADP-ribosylation factor GTPase activating protein 1; Cytohesin-1/2/3; bovine mammary epithelial cells; glutamine; mTORC1 pathway; milk protein synthesis
  6. Cancer Res. 2021 Jun 11. pii: canres.3792.2020. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC.
  7. Redox Biol. 2021 Jun 03. pii: S2213-2317(21)00187-7. [Epub ahead of print]45 102029
      Prolonged hyperglycemia plays a major role in the progression of β-cell loss in diabetes mellitus. Here we report an insulin sensitizer thiazolidinedione Pioglitazone selectively preserves the beta cells against high glucose-induced dysfunction by activation of AMPK and Glutaminase 1 (GLS1) axis. AMPK activation increases the stability of Glutaminase 1 by HSP90 family mitochondrial heat shock protein 75 (HSP75/TRAP1). This is associated with an elevation of GSH/GSSG ratio which leads to inhibition of mitochondrial dysfunction by induction of BCL2/BCL-XL in high glucose conditions. Pioglitazone was able to also protect against high glucose-induced elevations in maladaptive ER stress markers and increase the adaptive unfolded protein response (UPR) by inhibiting mTORC1-eEF2 protein translation machinery. Moreover, the pioglitazone effect on AMPK activation was not dependent on the PPARγ pathway. Strikingly, chemical inhibition of AMPK signaling or glutaminase-1 inhibition abrogates the pioglitazone effect on the TRAP1-GLS1 axis and GSH/GSSG ratio linked to mitochondrial dysfunction. Finally, inhibition of AMPK signaling enhanced maladaptive ER stress markers by mTORC1-eEF2 activation. Altogether, these results support the proposal that pioglitazone induced AMPK activation stabilizes a novel interaction of TRAP1/HSP75-GLS1 and its downstream signaling leads to improved β-cell function and survival under high glucose conditions.
    Keywords:  AMPK; Diabetes; Endoplasmic reticulum stress; Glutaminase; Oxidative stress; Pioglitazone