bims-glucam 2022-07-31 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–07–31
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.
GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors.
SLC38A6, regulated by EP300-mediated modifications of H3K27ac, promotes cell proliferation, glutamine metabolism, and mitochondrial respiration in hepatocellular carcinoma.
O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1.
hsa_circ_0000518 Facilitates Non-Small-Cell Lung Cancer Progression via Moderating miR-330-3p and Positively Regulating SLC1A5.
Rapid nutrient depletion to below the physiological range by cancer cells cultured in Plasmax.
Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.
Targeting AKT-Dependent Regulation of Antioxidant Defense Sensitizes AKT-E17K Expressing Cancer Cells to Ionizing Radiation.
Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.
Genetic, Metabolic and Immunological Features of Cancers with NRF2 Addiction.
GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma.
Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.
Role of Heme Oxygenase in Gastrointestinal Epithelial Cells.

Cell Commun Signal. 2022 Jul 27. 20(1): 114

Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.

Guofeng Ma, Zhilei Zhang, Peng Li, Zhao Zhang, Manqin Zeng, Zhijuan Liang, Dan Li, Liping Wang, Yuanbin Chen, Ye Liang, Haitao Niu.

  Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

Keywords:  Glutamine metabolism; Glutamine metabolism inhibitors; Immune response; Immunity; Reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-022-00909-0
Cancer Res. 2022 Jul 27. pii: CAN-22-0042. [Epub ahead of print]

GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors.

Yunzheng Li, Binghua Li, Yanchao Xu, Liyuan Qian, Tiancheng Xu, Gang Meng, Huan Li, Ye Wang, Laizhu Zhang, Xiang Jiang, Qi Liu, Yuanyuan Xie, Chunxiao Cheng, Beicheng Sun, Decai Yu.

Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and GSH synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0042
Carcinogenesis. 2022 Jul 28. pii: bgac061. [Epub ahead of print]

SLC38A6, regulated by EP300-mediated modifications of H3K27ac, promotes cell proliferation, glutamine metabolism, and mitochondrial respiration in hepatocellular carcinoma.

Li Huang, Lixing Li, Bin Cheng, Tonghai Xing.

  Hepatocellular carcinoma (HCC) is a common form of liver cancer. The incidence of HCC is increasing and effective prevention methods are needed. The solute carrier family 38 member 6 (SLC38A6) plays an important role in the metabolism of glutamine, which is a central nutrient for many cancers. However, the regulation and function of SLC38A6 in HCC are unclear. SLC38A6 levels in human HCC tissue arrays and cells were determined. SLC38A6 was silenced or overexpressed to determine its role in regulating cell viability, colony formation, cell cycle progression, glutamine metabolism, and mitochondrial respiration. A luminescence assay was used to study the interaction between SLC38A6 and EP300. The interactions between SLC38A6, H3K27ac, and EP300 were determined using chromatin immunoprecipitation assays. Quantitative RT-PCR and immunoblots were performed to measure mRNAs and proteins, respectively. SLC38A6 expression was higher in HCC compared with expression in normal tissue. Silencing SLC38A6 inhibited cell viability, colony formation, cell cycle progression, glutamine metabolism, and mitochondrial respiration, while SLC38A6 overexpression had the opposite effects. Silencing SLC38A6 also inhibited tumor growth in vivo. Silencing EP300 significantly suppressed the interaction between H3K27ac and the SLC38A6 promoter, leading to decreased SLC38A6. SLC38A6 is regulated by EP300-mediated modifications of H3K27ac and promotes viability, colony formation, cell cycle progression, glutamine metabolism, and mitochondrial respiration in HCC cells.

Keywords:  acetylation; glutamine metabolism; hepatocellular carcinoma; solute carrier family 38 member 6

DOI:  https://doi.org/10.1093/carcin/bgac061
Nat Chem Biol. 2022 Jul 25.

O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1.

Qiang Zhu, Hong Zhou, Liming Wu, Zhenyuan Lai, Didi Geng, Weiwei Yang, Jie Zhang, Zhiya Fan, Weijie Qin, Yong Wang, Ruhong Zhou, Wen Yi.

Oncogenic Kras-activated pancreatic ductal adenocarcinoma (PDAC) cells highly rely on an unconventional glutamine catabolic pathway to sustain cell growth. However, little is known about how this pathway is regulated. Here we demonstrate that Kras mutation induces cellular O-linked β-N-acetylglucosamine (O-GlcNAc), a prevalent form of protein glycosylation. Malate dehydrogenase 1 (MDH1), a key enzyme in the glutamine catabolic pathway, is positively regulated by O-GlcNAcylation on serine 189 (S189). Molecular dynamics simulations suggest that S189 glycosylation on monomeric MDH1 enhances the stability of the substrate-binding pocket and strengthens the substrate interactions by serving as a molecular glue. Depletion of O-GlcNAcylation reduces MDH1 activity, impairs glutamine metabolism, sensitizes PDAC cells to oxidative stress, decreases cell proliferation and inhibits tumor growth in nude mice. Furthermore, O-GlcNAcylation levels of MDH1 are elevated in clinical PDAC samples. Our study reveals that O-GlcNAcylation contributes to pancreatic cancer growth by regulating the metabolic activity of MDH1.

DOI: https://doi.org/10.1038/s41589-022-01085-5
J Immunol Res. 2022 ;2022 4996980

hsa_circ_0000518 Facilitates Non-Small-Cell Lung Cancer Progression via Moderating miR-330-3p and Positively Regulating SLC1A5.

Huilai Lv, Zhihua Shi, Aixia Sui, Yan Zhang, Liangbiao Peng, Mingbo Wang, Fan Zhang.

Background/Aim: Non-small-cell lung cancer (NSCLC) is the principal agent of cancer deaths globally. The goal of this study was to determine how circular RNA_0000518 (circ_0000518) regulates tumor progression. Materials/Methods. circ_0000518 was selected as a study target involved in NSCLC from GEO (Gene Expression Omnibus) database. circ_0000518 level was gauged by qRT-PCR. It was confirmed as circRNA by actinomycin D inhibition and RNase R assay. Subcellular localization of circ_0000518 was identified by FISH. Cell function was determined by CCK-8, Transwell, and western blot. Glutamine metabolic factors were detected by ELISA. The target regulation relationship between genes was clarified by dual-luciferase reporter assay. In vivo models were established to evaluate the impact of circ_0000518 on tumor growth. Immunohistochemical staining for Ki67, vimentin, and E-cadherin was used to detect cell proliferation and metastasis, respectively.
Results: circ_0000518 expression was enhanced in NSCLC. si-circ_0000518 inhibited cell proliferation, invasion, and glutamine metabolism. circ_0000518 functioned as a molecular sponge for miR-330-3p, and inhibition of miR-330-3p in cells markedly reversed circ_0000518 interference-mediated antitumor effects. miR-330-3p interacted with 3'-UTR of SLC1A5. miR-330-3p inhibitor-mediated protumor effect was remarkably reversed in cells after the knockdown of SLC1A5. circ_0000518 knockdown reduced glutamine, glutamate, and α-KG by targeting miR-330-3p. Intertumoral injection of circ_0000518 shRNA adeno-associated virus effectively halted xenograft tumor growth.
Conclusion: The current study revealed that circ_0000518 may have a prooncogenic function in the formation and progression of NSCLC, which might be achieved through moderating the miR-330-3p/SLC1A5 axis.

DOI: https://doi.org/10.1155/2022/4996980
Am J Physiol Cell Physiol. 2022 Jul 25.

Rapid nutrient depletion to below the physiological range by cancer cells cultured in Plasmax.

Georgina Gardner, Feresteh Moradi, Christopher Moffatt, Meagan Cliche, Bianca Garlisi, John Gratton, Fatima Mehmood, Jeffrey A Stuart.

  Mammalian cell culture is a fundamental tool used to study living cells. Presently, the standard protocol for performing cell culture involves the use of commercial media that contain an excess of nutrients. While this reduces the likelihood of cell starvation, it creates non-physiologic culture conditions that have been shown to 're-wire' cellular metabolism. Recently, researchers have developed new media like Plasmax, formulated to approximate the nutrient composition of human blood plasma. Although this represents an improvement in cell culture practice, physiologic media may be vulnerable to nutrient depletion. In this study we directly addressed this concern by measuring the rates of glucose and amino acid depletion from Plasmax in several cancer cell lines (PC-3, LNCaP, MCF-7, SH-SY5Y) over 48 hours. In all cell lines, depletion of glucose from Plasmax was rapid such that, by 48h, cells were hypoglycemic (<2mM glucose). Most amino acids were similarly rapidly depleted to sub-physiological levels by 48h. In contrast, glucose and most amino acids remained within the physiological range at 24h. When the experiment was done at physiological oxygen (5%) versus standard (18%)with LNCaP cells, no effect on glucose or amino acid consumption was observed. Using RNA sequencing, we show that this nutrient depletion is associated with enrichment of starvation responses, apoptotic signalling, and endoplasmic reticulum stress. A shift from glycolytic metabolism to mitochondrial respiration at 5% O2 was also measured using Seahorse analysis. Taken together, these results exemplify the metabolic considerations for Plasmax, highlighting that cell culture in Plasmax requires daily media exchange.

Keywords:  amino acids; metabolism; metabolomics; physiologic cell culture; physioxia

DOI:  https://doi.org/10.1152/ajpcell.00403.2021
Nutrients. 2022 Jul 22. pii: 3020. [Epub ahead of print]14(15):

Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.

Mario C Chang, Rohit Mahar, Marc A McLeod, Anthony G Giacalone, Xiumei Huang, David A Boothman, Matthew E Merritt.

  The compound β-lapachone, a naturally derived naphthoquinone, has been utilized as a potent medicinal nutrient to improve health. Over the last twelve years, numerous reports have demonstrated distinct associations of β-lapachone and NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in the amelioration of various diseases. Comprehensive research of NQO1 bioactivity has clearly confirmed the tumoricidal effects of β-lapachone action through NAD+-keresis, in which severe DNA damage from reactive oxygen species (ROS) production triggers a poly-ADP-ribose polymerase-I (PARP1) hyperactivation cascade, culminating in NAD+/ATP depletion. Here, we report a novel combination strategy with aminooxyacetic acid (AOA), an aspartate aminotransferase inhibitor that blocks the malate-aspartate shuttle (MAS) and synergistically enhances the efficacy of β-lapachone metabolic perturbation in NQO1+ breast cancer. We evaluated metabolic turnover in MDA-MB-231 NQO1+, MDA-MB-231 NQO1-, MDA-MB-468, and T47D cancer cells by measuring the isotopic labeling of metabolites from a [U-13C]glucose tracer. We show that β-lapachone treatment significantly hampers lactate secretion by ~85% in NQO1+ cells. Our data demonstrate that combinatorial treatment decreases citrate, glutamate, and succinate enrichment by ~14%, ~50%, and ~65%, respectively. Differences in citrate, glutamate, and succinate fractional enrichments indicate synergistic effects on central metabolism based on the coefficient of drug interaction. Metabolic modeling suggests that increased glutamine anaplerosis is protective in the case of MAS inhibition.

Keywords:  GC-MS; biogenic; cancer; isotopologue; metabolism; synergy

DOI:  https://doi.org/10.3390/nu14153020
Front Oncol. 2022 ;12 920017

Targeting AKT-Dependent Regulation of Antioxidant Defense Sensitizes AKT-E17K Expressing Cancer Cells to Ionizing Radiation.

Isabell Goetting, Safa Larafa, Katharina Eul, Mikhail Kunin, Burkhard Jakob, Johann Matschke, Verena Jendrossek.

  Aberrant activation of the phosphatidyl-inositol-3-kinase/protein kinase B (AKT) pathway has clinical relevance to radiation resistance, but the underlying mechanisms are incompletely understood. Protection against reactive oxygen species (ROS) plays an emerging role in the regulation of cell survival upon irradiation. AKT-dependent signaling participates in the regulation of cellular antioxidant defense. Here, we were interested to explore a yet unknown role of aberrant activation of AKT in regulating antioxidant defense in response to IR and associated radiation resistance. We combined genetic and pharmacologic approaches to study how aberrant activation of AKT impacts cell metabolism, antioxidant defense, and radiosensitivity. Therefore, we used TRAMPC1 (TrC1) prostate cancer cells overexpressing the clinically relevant AKT-variant AKT-E17K with increased AKT activity or wildtype AKT (AKT-WT) and analyzed the consequences of direct AKT inhibition (MK2206) and inhibition of AKT-dependent metabolic enzymes on the levels of cellular ROS, antioxidant capacity, metabolic state, short-term and long-term survival without and with irradiation. TrC1 cells expressing the clinically relevant AKT1-E17K variant were characterized by improved antioxidant defense compared to TrC1 AKT-WT cells and this was associated with increased radiation resistance. The underlying mechanisms involved AKT-dependent direct and indirect regulation of cellular levels of reduced glutathione (GSH). Pharmacologic inhibition of specific AKT-dependent metabolic enzymes supporting defense against oxidative stress, e.g., inhibition of glutathione synthase and glutathione reductase, improved eradication of clonogenic tumor cells, particularly of TrC1 cells overexpressing AKT-E17K. We conclude that improved capacity of TrC1 AKT-E17K cells to balance antioxidant defense with provision of energy and other metabolites upon irradiation compared to TrC1 AKT-WT cells contributes to their increased radiation resistance. Our findings on the importance of glutathione de novo synthesis and glutathione regeneration for radiation resistance of TrC1 AKT-E17K cells offer novel perspectives for improving radiosensitivity in cancer cells with aberrant AKT activity by combining IR with inhibitors targeting AKT-dependent regulation of GSH provision.

Keywords:  AKT; antioxidant defense; glutathione reductase; glutathione synthase; glycolysis; hexokinase 2; radioresistance

DOI:  https://doi.org/10.3389/fonc.2022.920017
Int J Oncol. 2022 Sep;pii: 108. [Epub ahead of print]61(3):

Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.

Tokio Terado, Chul Jang Kim, Akiyo Ushio, Kahori Minami, Yukihiro Tambe, Susumu Kageyama, Akihiro Kawauchi, Toshiyuki Tsunoda, Senji Shirasawa, Hiroyuki Tanaka, Hirokazu Inoue.

  Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three‑dimensional (3D)‑spheroid formation and in vivo tumorigenesis of KRAS‑activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT‑induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild‑type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild‑type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa‑2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D‑spheroid formation, the expression of acetyl‑CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione‑SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa‑2 cells, partially promoted ROS production and mildly suppressed 3D‑spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS‑dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS‑driven intractable cancers via alteration of cell metabolism.

Keywords:  KRAS; PDK4 inhibitor; acetyl‑CoA carboxylase 1; cryptotanshinone; fatty acid synthase; lipid synthesis; pancreatic neoplasm; reactive oxygen species

DOI:  https://doi.org/10.3892/ijo.2022.5398
FEBS Lett. 2022 Jul 27.

Genetic, Metabolic and Immunological Features of Cancers with NRF2 Addiction.

Hiroshi Kitamura, Haruna Takeda, Hozumi Motohashi.

  Nuclear factor erythroid-derived 2-like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumorigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant a cancer cell. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2-activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.

Keywords:  CEBPB; KEAP1; NOTCH3; NRF2; cancer stemness; immunoevasion; malignancy; metabolic reprogramming; non-small cell lung cancer; pentose phosphate pathway

DOI:  https://doi.org/10.1002/1873-3468.14458
Cancer Res. 2022 Jul 27. pii: CAN-21-3914. [Epub ahead of print]

GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma.

Carol Prives, Sawako Suzuki, Divya Venkatesh, Hiroaki Kanda, Akitoshi Nakayama, Hiroyuki Hosokawa, Eunyoung Lee, Takashi Miki, Brent R Stockwell, Koutaro Yokote, Tomoaki Tanaka.

Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepatocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type mice. GLS2 has been shown to promote ferroptosis, a form of cell death characterized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid ROS production by facilitating the conversion of glutamate to α-ketoglutarate, thereby promoting ferroptosis. Ectopic expression of wild-type GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3914
Cancers (Basel). 2022 Jul 22. pii: 3560. [Epub ahead of print]14(15):

Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.

Francesco Perri, Giuseppina Della Vittoria Scarpati, Monica Pontone, Maria Luisa Marciano, Alessandro Ottaiano, Marco Cascella, Francesco Sabbatino, Agostino Guida, Mariachiara Santorsola, Piera Maiolino, Ernesta Cavalcanti, Giulia Togo, Franco Ionna, Francesco Caponigro.

  Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it.

Keywords:  Akt; TP53; Warburg effect; head and neck squamous cell carcinoma; immunosurveillance; metabolic reprogramming

DOI:  https://doi.org/10.3390/cancers14153560
Antioxidants (Basel). 2022 Jul 05. pii: 1323. [Epub ahead of print]11(7):

Role of Heme Oxygenase in Gastrointestinal Epithelial Cells.

Reiko Akagi.

  The gastrointestinal tract is a unique organ containing both vascular and luminal routes lined by epithelial cells forming the mucosa, which play an important role in the entry of nutrients and act as a selective barrier, excluding potentially harmful agents. Mucosal surfaces establish a selective barrier between hostile external environments and the internal milieu. Heme is a major nutritional source of iron and is a pro-oxidant that causes oxidative stress. Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which are subsequently converted to bilirubin by biliverdin reductase. In gastrointestinal pathogenesis, HO-1, an inducible isoform of HO, is markedly induced in epithelial cells and plays an important role in protecting mucosal cells. Recent studies have focused on the biological effects of the products of this enzymatic reaction, which have antioxidant, anti-inflammatory, and cytoprotective functions. In this review, the essential roles of HO in the gastrointestinal tract are summarized, focusing on nutrient absorption, protection against cellular stresses, and the maintenance and regulation of tight junction proteins, emphasizing the potential therapeutic implications. The biochemical basis of the potential therapeutic implications of glutamine for HO-1 induction in gastrointestinal injury is also discussed.

Keywords:  barrier function; bilirubin; carbon monoxide; gastrointestinal epithelial cell; heat shock protein 70; heme oxygenase-1; oxidative stress

DOI:  https://doi.org/10.3390/antiox11071323