bims-glucam 2020-09-06 papers

Issue of 2020‒09‒06
four papers selected by
Sreeparna Banerjee
Middle East Technical University

Redox Biol. 2020 Jul 13. pii: S2213-2317(20)30848-X. [Epub ahead of print]36 101643

Metabolic reprogramming sustains cancer cell survival following extracellular matrix detachment.

Hitoshi Endo, Satoshi Owada, Yutaka Inagaki, Yukari Shida, Masayuki Tatemichi.

Epithelial cells require attachment to a support, such as the extracellular matrix, for survival. During cancer progression and metastasis, cancerous epithelial cells must overcome their dependence on adhesion signals. Dependence on glucose metabolism is a hallmark of cancer cells, but the nutrient requirements of cancer cells under anchorage-deficient conditions remain uncharacterized. Here, we report that cancer cells prioritize glutamine-derived tricarboxylic acid cycle energy metabolism over glycolysis to sustain anchorage-independent survival. Moreover, glutamine-dependent metabolic reprogramming is required not only to maintain ATP levels but also to suppress excessive oxidative stress through interaction with cystine. Mechanistically, AMPK, a central regulator of cellular responses to metabolic stress, participates in the induction of the expression of ASCT2, a glutamine transporter, and enhances glutamine consumption. Most interestingly, AMPK activation induces Nrf2 and its target proteins, allowing cancer cells to maintain energy homeostasis and redox status through glutaminolysis. Treatment with an integrin inhibitor was used to mimic the alterations in cell morphology and metabolic reprogramming caused by detachment. Under these conditions, cells were vulnerable to glutamine starvation or glutamine metabolism inhibitors. The observed preference for glutamine over glucose was more pronounced in aggressive cancer cell lines, and treatment with the glutaminase inhibitor, CB839, and cystine transporter inhibitor, sulfasalazine, caused strong cytotoxicity. Our data clearly show that anchorage-independent survival of cancer cells is supported mainly by glutaminolysis via the AMPK-Nrf2 signal axis. The discovery of new vulnerabilities along this route could help slow or prevent cancer progression.

Keywords: Anoikis; Extracellular matrix detachment; Glutaminolysis; Metabolic reprogramming; Metastasis

DOI: https://doi.org/10.1016/j.redox.2020.101643

Theranostics. 2020 ;10(21): 9458-9476

Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells.

Lutao Du, Xiaoyan Liu, Yidan Ren, Juan Li, Peilong Li, Qinlian Jiao, Peng Meng, Fang Wang, Yuli Wang, Yun-Shan Wang, Chuanxin Wang.

Rationale: It has been proposed that cancer stem/progenitor cells (or tumor-initiating cells, TICs) account for breast cancer initiation and progression. Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class-III histone deacetylases and mediate various basic biological processes, including metabolic homeostasis. However, interplay and cross-regulation among the sirtuin family are not fully understood. As one of the least studied sirtuin family members, the mitochondrial sirtuin SIRT4 is a tumor suppressor gene in various cancers. However, its role in cancer stemness, as well as initiation and progression of breast cancer, remains unknown. Methods: The expression of SIRT4 in breast cancer was analyzed using the TCGA breast cancer database and 3 GSEA data. Normal breast epithelial cells MCF10A and breast cancer cell lines MCF-7, MDA-MB-231, BT549, MDA-MB-468 were used to establish SIRT4 gene knockdown and corresponding overexpression cells. Identified MTT cytotoxicity assays, cell invasion and motility assay, sorting of SP, confocal immunofluorescence microscopy, mouse mammary stem cell analysis, glutamine and glucose production, clonogenic and sphere-formation assay, mass spectrometric metabolomics analysis and ChIP-seq to further explore SIRT4 biological role in breast cancer. Results: We elucidated a novel role for SIRT4 in the negative regulation of mammary gland development and stemness, which is related to the mammary tumorigenesis. We also uncovered an inverse correlation between SIRT4 and SIRT1. Most importantly, SIRT4 negatively regulates SIRT1 expression via repressing glutamine metabolism. Besides, we identified H4K16ac and BRCA1 as new prime targets of SIRT4 in breast cancer. Conclusions: These results demonstrate that SIRT4 exerts its tumor-suppressive activity via modulating SIRT1 expression in breast cancer and provide a novel cross-talk between mitochondrial and nuclear sirtuins.

Keywords: SIRT1; SIRT4; breast cancer; cancer stemness; glutamine metabolism

DOI: https://doi.org/10.7150/thno.44688

EMBO Mol Med. 2020 Sep 04. e11210

Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

Alessio Menga, Marina Serra, Simona Todisco, Carla Riera-Domingo, Ummi Ammarah, Manuel Ehling, Erika M Palmieri, Maria Antonietta Di Noia, Rosanna Gissi, Maria Favia, Ciro L Pierri, Paolo E Porporato, Alessandra Castegna, Massimiliano Mazzone.

Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2-like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti-tumor, M1-like, tumor-associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1-like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well-tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis.

Keywords: glufosinate; glutamine synthetase; immunometabolism; macrophages; metastasis

DOI: https://doi.org/10.15252/emmm.201911210

Clin Genet. 2020 Sep 04.

Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. Glutamine synthetase (GS) deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality foundin GLUL animal models. This article is protected by copyright. All rights reserved.

Keywords: 1q25.3 deletion; GLUL; Glutamine synthetase

DOI: https://doi.org/10.1111/cge.13844