bims-glucam 2022-02-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–02–27
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation.
Thyroid hormone regulates glutamine metabolism and anaplerotic fluxes by inducing mitochondrial glutamate aminotransferase GPT2.
HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation.
Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming.
TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.
The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells.
Glutamine-dependent signaling controls pluripotent stem cell fate.
PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1.
A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway.
Oncometabolites-A Link between Cancer Cells and Tumor Microenvironment.
Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.
Essential amino acids deprivation is a potential strategy for breast cancer treatment.
Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.

Adv Sci (Weinh). 2022 Feb 20. e2103887

Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation.

Hui-Lu Zhang, Ping Chen, He-Xin Yan, Gong-Bo Fu, Fei-Fei Luo, Jun Zhang, Shi-Min Zhao, Bo Zhai, Jiang-Hong Yu, Lin Chen, Hao-Shu Cui, Jian Chen, Shuai Huang, Jun Zeng, Wei Xu, Hong-Yang Wang, Jie Liu.

  Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient-derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem-like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non-TICs into stem-like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem-like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3-mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2-HDAC3-GS axis decrease TICs and promote xenografts regression upon glutamine-starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2-HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine-starvation therapy and limit the rapid growth and malignant progression of tumors.

Keywords:  HDAC3; Rictor/mTORC2; glutamine starvation; glutamine synthetase; tumor initiating cells

DOI:  https://doi.org/10.1002/advs.202103887
Cell Rep. 2022 Feb 22. pii: S2211-1247(22)00133-4. [Epub ahead of print]38(8): 110409

Thyroid hormone regulates glutamine metabolism and anaplerotic fluxes by inducing mitochondrial glutamate aminotransferase GPT2.

Annunziata Gaetana Cicatiello, Serena Sagliocchi, Annarita Nappi, Emery Di Cicco, Caterina Miro, Melania Murolo, Mariano Stornaiuolo, Monica Dentice.

  Thyroid hormones (THs) are key metabolic regulators coordinating short- and long-term energy needs. In skeletal muscle, THs modulate energy metabolism in pathophysiological conditions. Indeed, hypo- and hyperthyroidism are leading causes of muscle weakness and strength; however, the metabolic pathways underlying these effects are still poorly understood. Using molecular, biochemical, and isotope-tracing approaches combined with mass spectrometry and denervation experiments, we find that THs regulate glutamine metabolism and anaplerotic fluxes by up-regulating the glutamate pyruvate transaminase 2 (GPT2) gene. In humans, GPT2 autosomal recessive mutations cause a neurological syndrome characterized by intellectual disability, microcephaly, and progressive motor symptoms. Here, we demonstrate a role of the TH/GPT2 axis in skeletal muscle in which it regulates muscle weight and fiber diameter in resting and atrophic conditions and results in protection from muscle loss during atrophy. These results describe an anabolic route by which THs rewire glutamine metabolism toward the maintenance of muscle mass.

Keywords:  GPT2; glutamine metabolism; skeletal muscle; thyroid hormone; type 2 deiodinase

DOI:  https://doi.org/10.1016/j.celrep.2022.110409
Int J Oncol. 2022 Apr;pii: 37. [Epub ahead of print]60(4):

HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation.

Zhenting He, Yingying Gao, Ting Li, Chaowen Yu, Liping Ou, Chunli Luo.

  Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell‑dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) and gas chromatography‑mass spectrometry (GC‑MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress‑resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK‑8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.

Keywords:  5‑bisphosphate 3‑kinase catalytic subunit α; glutamine metabolic reprogramming; hepatocellular cell adhesion molecule; phosphatidylinositol‑4; proliferation; prostate cancer

DOI:  https://doi.org/10.3892/ijo.2022.5327
J Mol Med (Berl). 2022 Feb 25.

Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming.

Yueying Yang, Mengzhu Zheng, Fei Han, Lei Shang, Mingxue Li, Xiaoxia Gu, Hua Li, Lixia Chen.

  Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor whose effective treatment has not been found. The redox state and proliferative activity of PDAC cells are maintained by the conversion of aspartic acid in the cytoplasm into oxaloacetate though aspartate aminotransferase 1 (GOT1). Therefore, GOT1 inhibitors as a potential approach for treating PDAC have attracted more attention of researchers. Ziprasidone effectively inhibited GOT1 in a non-competitive manner. The potential cytotoxicity and anti-proliferation effects of ziprasidone against PDAC cells in vitro and in vivo were evaluated. Ziprasidone can induce glutamine metabolism disorder and redox state imbalance of PDAC cells by targeting GOT1, thereby inhibiting proliferation, preventing migration, and inducing apoptosis. Ziprasidone displayed significant in vivo antitumor efficacy in SW1990 cell-derived xenografts. What's more, knockdown of GOT1 in SW1990 reduced the anti-proliferative effects of ziprasidone. As a novel GOT1 inhibitor, ziprasidone may be a lead compound for the treatment of PDAC. KEY MESSAGES: Small molecule inhibitors targeting GOT1 may provide a therapeutic target in PDAC. Ziprasidone effectively inhibited GOT1 enzyme in a non-competitive manner. Ziprasidone repressed glutamine metabolism and inhibited the growth of tumor in vivo. Knockdown of GOT1 decreased the anti-proliferative effects of ziprasidone.

Keywords:  GOT1 inhibitor; Glutamine metabolism; Metabolomics analysis; Pancreatic cancer; Ziprasidone

DOI:  https://doi.org/10.1007/s00109-022-02181-8
Metabolites. 2022 Jan 21. pii: 101. [Epub ahead of print]12(2):

TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.

Suvithanandhini Loganathan, Bryce A Wilson, Sara B Carey, Ernesto Manzo, Archi Joardar, Berrak Ugur, Daniela C Zarnescu.

  Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a Drosophila model of ALS based on TDP-43 expression in motor neurons that recapitulates hallmark features of motor neuron disease including TDP-43 aggregation, locomotor dysfunction, and reduced lifespan. To gain insights into metabolic changes caused by TDP-43, we performed global metabolomic profiling in larvae expressing TDP-43 (WT or ALS associated mutant variant, G298S) and identified significant alterations in several metabolic pathways. Here, we report alterations in multiple metabolic pathways and highlight upregulation of Tricarboxylic acid (TCA) cycle metabolites and defects in neurotransmitter levels. We also show that modulating TCA cycle flux either genetically or by dietary intervention mitigates TDP-43-dependent locomotor defects. In addition, dopamine levels are significantly reduced in the context of TDP-43G298S, and we find that treatment with pramipexole, a dopamine agonist, improves locomotor function in vivo in Drosophila models of TDP-43 proteinopathy.

Keywords:  Amyotrophic lateral sclerosis (ALS); Tricarboxylic acid (TCA) cycle; dopamine; glutamine; metabolic alterations; pramipexole; pyruvate

DOI:  https://doi.org/10.3390/metabo12020101
Biomedicines. 2022 Feb 01. pii: 348. [Epub ahead of print]10(2):

The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells.

Stéphanie Nuan-Aliman, Didier Bordereaux, Catherine Thieblemont, Véronique Baud.

  Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main pathways, the canonical and the alternative NF-κB pathways, the main actor of the latter being the RelB NF-kB subunit. RelB DNA binding activity is frequently activated in DLBCL patients and cell lines. RelB activation defines a new DLBCL subgroup with dismal outcome upon immunochemotherapy, and RelB confers DLBCL cell resistance to DNA damage. However, whether RelB can impact on DLBCL cell metabolism and survival upon metabolic stress is unknown. Here, we reveal that RelB controls DLBCL oxidative energetic metabolism. Accordingly, RelB inhibition reduce DLBCL mitochondrial ATP production, and sensitizes DLBCL cells to apoptosis induced by Metformin and L-asparaginase (®Kidrolase), two FDA approved antimetabolic drugs targeting mitochondrial metabolism. RelB also confers DLBCL cell resistance to glutamine deprivation, an essential amino acid that feeds the TCA cycle. Taken together, our findings uncover a new role for RelB in the regulation of DLBCL cell metabolism and DLBCL cell survival upon metabolic stress.

Keywords:  DLBCL; NF-κB; RelB; apoptosis; lymphoma; metabolism

DOI:  https://doi.org/10.3390/biomedicines10020348
Dev Cell. 2022 Feb 15. pii: S1534-5807(22)00069-7. [Epub ahead of print]

Glutamine-dependent signaling controls pluripotent stem cell fate.

Vivian Lu, Irena J Roy, Alejandro Torres, James H Joly, Fasih M Ahsan, Nicholas A Graham, Michael A Teitell.

  Human pluripotent stem cells (hPSCs) can self-renew indefinitely or can be induced to differentiate. We previously showed that exogenous glutamine (Gln) withdrawal biased hPSC differentiation toward ectoderm and away from mesoderm. We revealed that, although all three germ lineages are capable of de novo Gln synthesis, only ectoderm generates sufficient Gln to sustain cell viability and differentiation, and this finding clarifies lineage fate restrictions under Gln withdrawal. Furthermore, we found that Gln acts as a signaling molecule for ectoderm that supersedes lineage-specifying cytokine induction. In contrast, Gln in mesoderm and endoderm is the preferred precursor of α-ketoglutarate without a direct signaling role. Our work raises a question about whether the nutrient environment functions directly in cell differentiation during development. Interestingly, transcriptome analysis of a gastrulation-stage human embryo shows that unique Gln enzyme-encoding gene expression patterns may also distinguish germ lineages in vivo. Together, our study suggests that intracellular Gln may help coordinate differentiation of the three germ layers.

Keywords:  auxotroph; cell fate; development; glutamine; nutrient; pluripotent stem cell; prototroph

DOI:  https://doi.org/10.1016/j.devcel.2022.02.003
Theranostics. 2022 ;12(4): 1589-1606

PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1.

Shuai Wang, Yanke Lin, Lu Gao, Zemin Yang, Jingpan Lin, Shujing Ren, Feng Li, Jing Chen, Zhigang Wang, Zhiyong Dong, Pinghua Sun, Baojian Wu.

  While growing evidence suggests that circadian clock and obesity are intertwined, the underlying mechanism is poorly understood. Here, we investigate how circadian clock is linked to obesity. Methods: Metabolomics profiling of WAT (white adipose tissue) samples was performed to identify the metabolites altered in obese model. mRNA levels were analyzed by qPCR assays. Proteins were detected by immunoblotting, immunofluorescence and ELISA. ChIP and luciferase reporter assays were used to investigate epigenetic and transcriptional regulation. Results: Obesity causes perturbance of circadian clock in WAT in mice and humans, particularly, BMAL1 is markedly reduced. Metabolomic analysis reveals reduced glutamine and methionine in obese WAT. Glutamine metabolism contributes to production of acetyl-CoA, whereas methionine metabolism generates S-adenosyl methionine (SAM). Acetyl-CoA and SAM are the substrates for histone acetylation and methylation, respectively. Reduced glutamine and methionine in obese WAT are associated with decreased H3K27ac and H3K4me3 at Bmal1 promoter. Consistently, glutamine or methionine administration in vitro and in vivo increases H3K27ac or H3K4me3, promoting Bmal1 transcription and expression. A screen of transport and metabolic genes identifies downregulation of the uptake transporter SLC1A5 as a cause of reduced glutamine or methionine in obese WAT. Moreover, we observe impaired expression of PPAR-γ in obese WAT. PPAR-γ trans-activates Slc1a5 via direct binding to a response element in promoter. Conclusion: Impaired PPAR-γ in obesity provokes downregulation of SLC1A5 and reductions in adipocyte uptake of glutamine and methionine (two epigenetic modulators), leading to disruption of Bmal1. Therefore, PPAR-γ integrates obesity and adipocyte clock, promoting a vicious cycle between circadian disruption and obesity development.

Keywords:  BMAL1; PPAR-γ; SLC1A5; circadian clock; obesity

DOI:  https://doi.org/10.7150/thno.69054
Oncogene. 2022 Feb 23.

A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway.

Siqi Wu, Binbin Guo, Liyuan Zhang, Xun Zhu, Peipei Zhao, Jieqiong Deng, Jian Zheng, Fang Li, Yirong Wang, Shenghua Zhang, Zheng Zhang, Jiachun Lu, Yifeng Zhou.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with a poor prognosis. To date, the mechanism of TNBC's aggressive phenotype is still unclear. Based on metabolome analysis, we found that glutamine (Gln) metabolism plays a key role in the difference between TNBC and non-TNBC. We identified a 21-amino-acid survival-associated micropeptide XBP1SBM, encoded by the lncRNA MLLT4-AS1, which was upregulated in TNBC tissues and Gln-deprived TNBC cell lines. We showed that XBP1SBM expression was upregulated by Gln-deprivation-induced XBP1s transcriptional promotion, and in turn retained XBP1s in the nuclear to enhance the expression of VEGF. Using human endothelial cells, mouse xenograft models and mouse spontaneous BC models, we found that XBP1SBM improved Gln levels and promoted angiogenesis and metastasis in TNBC. Our study showed that a TNBC-specific nutrient deficiency adaption results in aggressive TNBC, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in TNBC.

DOI: https://doi.org/10.1038/s41388-022-02229-6
Biology (Basel). 2022 Feb 09. pii: 270. [Epub ahead of print]11(2):

Oncometabolites-A Link between Cancer Cells and Tumor Microenvironment.

Maksymilian Baryła, Aleksandra Semeniuk-Wojtaś, Letycja Róg, Leszek Kraj, Maciej Małyszko, Rafał Stec.

  The tumor microenvironment is the space between healthy tissues and cancer cells, created by the extracellular matrix, blood vessels, infiltrating cells such as immune cells, and cancer-associated fibroblasts. These components constantly interact and influence each other, enabling cancer cells to survive and develop in the host organism. Accumulated intermediate metabolites favoring dysregulation and compensatory responses in the cell, called oncometabolites, provide a method of communication between cells and might also play a role in cancer growth. Here, we describe the changes in metabolic pathways that lead to accumulation of intermediate metabolites: lactate, glutamate, fumarate, and succinate in the tumor and their impact on the tumor microenvironment. These oncometabolites are not only waste products, but also link all types of cells involved in tumor survival and progression. Oncometabolites play a particularly important role in neoangiogenesis and in the infiltration of immune cells in cancer. Oncometabolites are also associated with a disrupted DNA damage response and make the tumor microenvironment more favorable for cell migration. The knowledge summarized in this article will allow for a better understanding of associations between therapeutic targets and oncometabolites, as well as the direct effects of these particles on the formation of the tumor microenvironment. In the future, targeting oncometabolites could improve treatment standards or represent a novel method for fighting cancer.

Keywords:  fumarate; glutamate; lactate; oncometabolite; succinate

DOI:  https://doi.org/10.3390/biology11020270
Biomolecules. 2022 Feb 12. pii: 297. [Epub ahead of print]12(2):

Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.

Srinath Muralidharan, Sarthak Sahoo, Aryamaan Saha, Sanjay Chandran, Sauma Suvra Majumdar, Susmita Mandal, Herbert Levine, Mohit Kumar Jolly.

  Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis. Both partial and complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among the oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways and their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show the diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. The analysis of single-cell data for EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Further, assessing the association of EMT and metabolic activity with patient survival shows that a higher extent of EMT and glycolysis predicts a worse prognosis in many cancers. Together, our results reveal the underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.

Keywords:  AMPK; HIF1α; cancer metabolism; epithelial–mesenchymal transition; fatty acid metabolism; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom12020297
Breast. 2022 Feb 20. pii: S0960-9776(22)00036-4. [Epub ahead of print]62 152-161

Essential amino acids deprivation is a potential strategy for breast cancer treatment.

Yajie Zhao, Chunrui Pu, Zhenzhen Liu.

   AIMS: The study aimed to search novel, simple and practical index reflecting the level of essential amino acids (EAAs) metabolism in breast cancer (BC), as well as to explore the effect of enhanced EAAs metabolism on the prognosis and immune microenvironment of BC, thus providing new evidence for the application of EAAs deprivation in the BC treatment.
METHODS: The study includes the analysis of multi-omics and clinical data of 13 BC cell lines and 2898 BC patients in the public database. Further validation was performed using multi-omics and immunohistochemistry data from 83 BC tissue samples collected at our hospital.
RESULTS: According to the multi-omics data, the SLC7A5 to SLC7A8 Ratio (SSR) score was found to be significantly correlated with the EAAs level and EAAs-metabolic activity of BC, suggesting that the SSR score might be used as a biomarker to assess the degree of EAAs metabolism in BC. Besides, BC patients with high EAAs metabolism had shorter overall survival (OS) time, higher PD-L1 expression, and higher T regulatory cells (Tregs) infiltration, indicating that a high EAAs metabolism was related to a poor prognosis and immune suppression in BC. Additionally, MYC amplification is a critical molecular process in the metabolic reprogramming of EAAs in BC.
CONCLUSION: EAAs may be a possible therapeutic target for BC treatment.

Keywords:  Breast cancer; Essential amino acid; Metabolic reprogramming; PD-L1; Tregs

DOI:  https://doi.org/10.1016/j.breast.2022.02.009
FASEB J. 2022 03;36(3): e22211

Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.

Steffen H Raun, Jonas Roland Knudsen, Xiuqing Han, Thomas E Jensen, Lykke Sylow.

  Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.

Keywords:  AMPK; Akt; Lewis lung carcinoma; TBC1D4; cachexia; cancer; glucose metabolism; insulin resistance; mTORC1; muscle

DOI:  https://doi.org/10.1096/fj.202101759R