bims-glucam 2022-05-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–05–01
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine, MTOR and autophagy: a multiconnection relationship.
Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.
Characterization of metabolic alterations of Chronic Lymphocytic Leukemia in the lymph node microenvironment.
CircRNA OXCT1 promotes the malignant progression and glutamine metabolism of non-small cell lung cancer by absorbing miR-516b-5p and upregulating SLC1A5.
Choline Kinase Alpha2 Promotes Lipid Droplet Lipolysis in Non-Small-Cell Lung Carcinoma.
Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.
Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model.
Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer.
Current status of cancer starvation therapy.
Metabolism in tumor-associated macrophages.
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.
Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
Regulation of Intrinsic and Extrinsic Metabolic Pathways in Tumor-Associated Macrophages.
Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.

Autophagy. 2022 Apr 26. 1-2

Glutamine, MTOR and autophagy: a multiconnection relationship.

Clément Bodineau, Mercedes Tomé, Piedad Del Socorro Murdoch, Raúl V Durán.

  Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates MTORC1. The AMPK-MTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase (glutamine-hydrolyzing)) and the GABA shunt for the metabolic control of the AMPK-MTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the MTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.

Keywords:  ASNS; GABA-shunt; MTORC1; glutamine; glutamoptosis

DOI:  https://doi.org/10.1080/15548627.2022.2062875
Biochem Biophys Res Commun. 2022 Apr 20. pii: S0006-291X(22)00597-6. [Epub ahead of print]611 99-106

Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.

Issei Kawakami, Hirofumi Yoshino, Wataru Fukumoto, Motoki Tamai, Shunsuke Okamura, Yoichi Osako, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Masayuki Nakagawa, Hideki Enokida.

  In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC.

Keywords:  Cellular senescence; Glutamine transporter; Renal cell carcinoma; Solute carrier family 1 member 5; V9302

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.068
Blood. 2022 Apr 29. pii: blood.2021013990. [Epub ahead of print]

Characterization of metabolic alterations of Chronic Lymphocytic Leukemia in the lymph node microenvironment.

Zhenghao Chen, Helga Simon-Molas, Gaspard Cretenet, Beatriz Valle-Argos, Lindsay D Smith, Francesco Forconi, Bauke V Schomakers, Michel van Weeghel, Dean Bryant, Jaco A C van Bruggen, F S Peters, Jeffrey C Rathmell, G J W van der Windt, Arnon P Kater, Graham Packham, Eric Eldering.

Altered metabolism is one of the hallmarks of cell division and of cancer. CLL cells circulate between peripheral blood (PB) and lymph nodes (LN), where they receive proliferative and pro-survival signals from surrounding cells. Yet insight into the metabolism of LN CLL and how this may relate to therapeutic responses is lacking. To obtain insight into CLL LN metabolism, we applied a two-tiered strategy. First, we sampled PB from 8 patients at baseline, and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment, and performed metabolomics and transcriptomics. The combined analyses indicated prominent changes in purine, glucose and glutamate metabolism occurring in the LN. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA) and energy production. BCR signaling preferably engaged glucose and glycerol metabolism, and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation versus IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C-fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle while glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Altogether, these data provide insight into crucial metabolic changes driven by CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.

DOI: https://doi.org/10.1182/blood.2021013990
Cell Cycle. 2022 Apr 28.

CircRNA OXCT1 promotes the malignant progression and glutamine metabolism of non-small cell lung cancer by absorbing miR-516b-5p and upregulating SLC1A5.

Hua Luo, Jianming Peng, Yuexi Yuan.

   BACKGROUND: Previous study has demonstrated the high expression of circular RNA 3-oxoacid CoA-transferase 1 (circ-OXCT1) in lung adenocarcinoma tumor tissues. However, the role and possible mechanism of circ-OXCT1 in non-small cell lung cancer (NSCLC) progression was unclear.
METHODS: Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) staining assay were performed to detect the expression of circ-OXCT1, microRNA-516b-5p (miR-516b-5p), solute carrier family 1 member 5 (SLC1A5) and other indicated protein markers. Cell proliferation was measured by Cell counting kit 8 (CCK8), colony formation and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Flow cytometry was employed to detect the rate of apoptotic cells. Cell migration and invasion were measured using transwell assay. The relative glutamine uptake and α-ketoglutarate (α-KG) production was determined using commercial kits. Interaction between miR-516b-5p and circ-OXCT1 or SLC1A5 was predicted by bioinformatics analysis and confirmed via luciferase reporter and RNA immunoprecipitation (RIP) assays. In vivo assay was implemented to demonstrate the effect of circ-OXCT1 in tumor growth.
RESULTS: Circ-OXCT1 and SLC1A5 were upregulated and miR-516b-5p was downregulated in NSCLC tissues and cells. Functional experiments revealed that circ-OXCT1 silencing suppressed cell proliferation, migration and invasion, but promoted cell apoptosis in vitro. Circ-OXCT1 knockdown repressed tumor formation in vivo. Besides, miR-516b-5p was a target of circ-OXCT1, and miR-516b-5p inhibitor could relieve circ-OXCT1 absence-mediated effects in NSCLC cells. SLC1A5 was identified as a target of miR-516b-5p. Circ-OXCT1 promoted SLC1A5 expression by target binding with miR-516b-5p.
CONCLUSION: Circ-OXCT1 facilitated NSCLC progression via miR-516b-5p-dependent regulation of SLC1A5, which provided a possible circRNA-targeted therapy for NSCLC.

Keywords:  Circ-OXCT1; MiR-516b-5p; NSCLC

DOI:  https://doi.org/10.1080/15384101.2022.2071565
Front Oncol. 2022 ;12 848483

Choline Kinase Alpha2 Promotes Lipid Droplet Lipolysis in Non-Small-Cell Lung Carcinoma.

Rongxuan Zhu, Yannan Yang, Fei Shao, Juhong Wang, Yibo Gao, Jie He, Zhimin Lu.

   Background: Rapid tumor growth inevitably results in energy stress, including deficiency of glutamine, a critical amino acid for tumor cell proliferation. However, whether glutamine deficiency allows tumor cells to use lipid droplets as an energy resource and the mechanism underlying this potential regulation remain unclear.
Methods: We purified lipid droplets from H322 and H358 human non-small-cell lung cancer (NSCLC) cells under glutamine deprivation conditions and performed immunoblotting to determine the binding of choline kinase (CHK) α2 to lipid droplets. Immunofluorescence was used to quantify lipid droplet numbers and sizes. Immunoprecipitation and immunoblotting were performed to examine AMPK activation and CHKα2 phosphorylation. Cellular fatty acid levels, mitochondrial acetyl coenzyme A and ATP production, and cell apoptosis and proliferation were measured. Immunohistochemical analyses were performed to determine the expression levels of ACC pS79 and CHKα2 pS279 in tumor specimens from NSCLC patients. The prognostic value of ACC pS79 and CHKα2 pS279 was assessed using the Kaplan-Meier method and Cox regression models.
Results: Glutamine deficiency induces AMPK-mediated CHKα2 S279 phosphorylation, which promotes the binding of CHKα2 to lipid droplets, resulting in recruitment of cytosolic lipase ATGL and autophagosomes and subsequent lipolysis of lipid droplets to sustain tumor cell survival and proliferation. In addition, the levels of ACC pS79 and CHKα S279 were much higher in human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other. Notably, ACC pS79 and CHKα pS279 expression levels alone were associated with poor prognosis of NSCLC patients, and combined values of both phosphorylation levels were correlated with worse prognosis of the patients.
Conclusion: CHKα2 plays a critical role in lipolysis of lipid droplets in NSCLC. ACC pS79 and CHKα2 pS279 alone or in combination can be used as prognostic markers in NSCLC.

Keywords:  choline kinase; lipid metabolism; non-small-cell lung cancer; phosphorylation; prognostic biomarker

DOI:  https://doi.org/10.3389/fonc.2022.848483
J Drug Target. 2022 Apr 28. 1-28

Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.

Gang Wang, Wang Jun-Jie, Xiao-Na Xu, Feng Shi, Fu Xing-Li.

  Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumor microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumor cells and even enhance their aggressive phenotype. This review summarizes the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumor ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumor cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumor cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumor therapies for colorectal cancer.

Keywords:  Colorectal cancers; energy metabolism; small molecule compounds; tumor ferroptosis

DOI:  https://doi.org/10.1080/1061186X.2022.2071909
Korean J Physiol Pharmacol. 2022 May 01. 26(3): 145-155

Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model.

Xin-Li Liang, Miao-Miao Ji, Zheng-Gen Liao, Guo-Wei Zhao, Xi-Lan Tang, Wei Dong.

  Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.

Keywords:  Doxorubicin; Imperatorin; Leukemia; Multidrug resistance; P-glycoprotein

DOI:  https://doi.org/10.4196/kjpp.2022.26.3.145
Front Pharmacol. 2022 ;13 879751

Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer.

Lang Xie, Renli Huang, Hongyun Huang, Xiaoxia Liu, Jinlong Yu.

  Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy. Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined. Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options. Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.

Keywords:  cancer-associated fibroblasts; colorectal cancer; metabolomics; transcriptomics; tumor dormancy

DOI:  https://doi.org/10.3389/fphar.2022.879751
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Jan 25. 50(7): 1-11

Current status of cancer starvation therapy.

Jianyi Li, Dandan Tong, Junsheng Lin.

  Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive cancer cells of nutritional supply. There are several approaches to"starve" cancer cells: to intervene tumor angiogenesis by targeted inhibition of angiogenic factors or their receptors and integrins; to block the blood supply of cancer cells by embolizing or compressing blood vessels; to intervene metabolic process of cancer cells by inhibition of the signal pathways of mitochondrial serine-glycine-one earbon metabolism, glycolysis and amino acid metabolism; cancer starvation therapy can be employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-autophagy therapy or other therapies to achieve synergistic effects. This article reviews the research progress of cancer starvation therapy in recent years and discusses the existing problems.

Keywords:  Anti-angiogenesis; Neoplasms; Review; Starvation therapy; Synergistic therapy; Tumor metabolism

DOI:  https://doi.org/10.3724/zdxbyxb-2021-0297
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00004-1. [Epub ahead of print]367 65-100

Metabolism in tumor-associated macrophages.

Jie Li, Gina M DeNicola, Brian Ruffell.

  Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.

Keywords:  Immunometabolism; Metabolic reprogramming; Metabolism; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/bs.ircmb.2022.01.004
Sci Immunol. 2022 Apr 29. 7(70): eabm8161

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.

Xuyong Chen, Benjamin Sunkel, Meng Wang, Siwen Kang, Tingting Wang, J N Rashida Gnanaprakasam, Lingling Liu, Teresa A Cassel, David A Scott, Ana M Muñoz-Cabello, Jose Lopez-Barneo, Jun Yang, Andrew N Lane, Gang Xin, Benjamin Z Stanton, Teresa W-M Fan, Ruoning Wang.

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.

DOI: https://doi.org/10.1126/sciimmunol.abm8161
Acta Biomater. 2022 Apr 20. pii: S1742-7061(22)00231-8. [Epub ahead of print]

Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.

Xiangyu Meng, Zhuoxuan Lu, Qingyu Lv, Yongqiang Jiang, Liming Zhang, Zhifei Wang.

  Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met-based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met-based or GOx-mediated monotherapy.

Keywords:  Metformin; glycolysis inhibition; modified zeolitic imidazolate framework-8; starvation therapy; tumor metabolism

DOI:  https://doi.org/10.1016/j.actbio.2022.04.022
FEBS J. 2022 Apr 29.

Regulation of Intrinsic and Extrinsic Metabolic Pathways in Tumor-Associated Macrophages.

Goutham Venkata Naga Davuluri, Chia-Hsin Chan.

  Tumor-associated macrophages (TAMs) are highly plastic and are broadly grouped into two major functional states, namely the pro-inflammatory M1-type and the pro-tumoral M2-type. Conversion of the functional states of TAMs is regulated by various cytokines, chemokines growth factors, and other secreted factors in the microenvironment. Dysregulated metabolism is a hallmark of cancer. Emerging evidence suggests that metabolism governs the TAM differentiation and functional conversation in support of tumor growth and metastasis. Aside from the altered metabolism reprogramming in TAMs, extracellular metabolites secreted by cancer, stromal, and/or other cells within the tumor microenvironment have been found to regulate TAMs through passive competition for metabolite availability and direct regulation via receptor/transporter-mediated signaling reaction. In this review, we focus on the regulatory roles of different metabolites and metabolic pathways in TAM conversion and function. We also discuss if the dysregulated metabolism in TAMs can be exploited for the development of new therapeutic strategies against cancer.

Keywords:  immunotherapy; macrophage polarization and conversion; metabolic pathways; tumor-associated macrophages

DOI:  https://doi.org/10.1111/febs.16465
Nat Cancer. 2022 Apr;3(4): 453-470

Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.

Jiang Li, Yingying Ye, Zhihan Liu, Guoyang Zhang, Huiqi Dai, Jiaqian Li, Boxuan Zhou, Yihong Li, Qiyi Zhao, Jingying Huang, Jingwei Feng, Shu Liu, Peigang Ruan, Jinjing Wang, Jiang Liu, Min Huang, Xinwei Liu, Shubin Yu, Ziyang Liang, Liping Ma, Xiaoxia Gou, Guoliang Zhang, Nian Chen, Yiwen Lu, Can Di, Qidong Xia, Jiayao Pan, Ru Feng, Qingqing Cai, Shicheng Su.

Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.

DOI: https://doi.org/10.1038/s43018-022-00354-5