bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–08–06
nine papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Boosting the therapy of glutamine-addiction glioblastoma by combining glutamine metabolism therapy with photo-enhanced chemodynamic therapy.
  2. Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
  3. The regulation of amino acid metabolism in tumor cell death: from the perspective of physiological functions.
  4. Comparison of glutaminase and CA-125 in distinguishing benign and malignant ovarian tumors.
  5. Mapping metabolic perturbations induced by glutathione activatable synthetic ion channels in human breast cancer cells.
  6. Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.
  7. SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation.
  8. Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.
  9. Cancer cell plasticity during tumor progression, metastasis and response to therapy.
  1. Biomater Sci. 2023 Aug 03.
    Boosting the therapy of glutamine-addiction glioblastoma by combining glutamine metabolism therapy with photo-enhanced chemodynamic therapy.
    Ling Wang, Yaobao Han, Zhengpeng Gu, Mengxiao Han, Chunhong Hu, Zhen Li.
      The complete treatment of high grade invasive glioblastoma (GBM) remains to be a great challenge, and it is of great importance to develop innovative therapeutic approaches. Herein, we found that GBM derived from U87 MG cells is a glutamine-addiction tumor, and jointly using glutamine-starvation therapy and photo-enhanced chemodynamic therapy (CDT) can significantly boost its therapy. We rationally fabricated tumor cell membrane coated Cu2-xSe nanoparticles (CS NPs) and an inhibitor of glutamine metabolism (Purpurin) for combined therapy, because glutamine rather than glucose plays a crucial role in the proliferation and growth of GBM cells, and serves as a precursor for the synthesis of glutathione (GSH). The resultant CS-P@CM NPs can be specifically delivered to the tumor site to inhibit glutamine metabolism in tumor cells, suppress tumor intracellular GSH, and increase H2O2 content, which benefit the CDT catalyzed by CS NPs. The cascade reaction can be further enhanced by irradiation with the second near-infrared (NIR-II) light at the maximum concentration of H2O2, which can be monitored by photoacoustic imaging. The NIR-II light irradiation can generate a large amount of reactive oxygen species (ROS) within a short time to kill tumor cells and enhance the CDT efficacy. This is the first work on the treatment of orthotopic malignant GBM through combined glutamine metabolism therapy and photo-enhanced CDT, and provides insights into the treatment of other solid tumors by modulating the metabolism of tumor cells.
    DOI:  https://doi.org/10.1039/d3bm00897e
  2. Cell Death Dis. 2023 Aug 02. 14(8): 492
    Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
    Mei-Xin Li, Xiao-Ting Wu, Wen-Qiang Jing, Wen-Kui Hou, Sheng Hu, Wei Yan.
      Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.
    DOI:  https://doi.org/10.1038/s41419-023-06017-2
  3. Apoptosis. 2023 Jul 31.
    The regulation of amino acid metabolism in tumor cell death: from the perspective of physiological functions.
    Jin Wang, Hongying Wang, Min Gao, Yilei Zhang, Lei Zhang, Dongsheng Huang, Kangsheng Tu, Qiuran Xu.
      Amino acids (AAs) are crucial molecules for the synthesis of mammalian proteins as well as a source of energy and redox equilibrium maintenance. The development of tumors also requires AAs as nutrients. Increased AAs metabolism is frequently seen in tumor cells to produce enough biomass, energy, and reduction agents. However, increased AA demand may result in auxotrophy in some cancer cells, highlighting the vulnerabilities of cancers and exposing the AA metabolism as a potential target for cancer therapy. The dynamic balance of cell survival and death is required for cellular homeostasis, growth, and development. Malignant cells manage to avoid cell death through a range of mechanisms, such as developing an addiction to amino acids through metabolic adaptation. In order to offer some guidance for AA-targeted cancer therapy, we have outlined the function of AA metabolism in tumor progression, the modalities of cell death, and the regulation of AA metabolism on tumor cell death in this review.
    Keywords:  Amino acids; Cancer; Cancer therapy; Cell death modality; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s10495-023-01875-9
  4. Clin Transl Sci. 2023 Aug 01.
    Comparison of glutaminase and CA-125 in distinguishing benign and malignant ovarian tumors.
    Gatot Nyarumenteng Adhipurnawan Winarno, Jusuf Sulaeman Effendi, Ali Budi Harsono, Siti Salima, Bagja Dumas Darwizar, R M Sonny Sasotya, Anita Rachmawati, Ayu Insafi Mulyantari, Nurvita Trianasari, Budi Handono.
      Increasing demand for glutaminase (GLS) due to high rates of glutamine metabolism is considered one of the hallmarks of malignancy. In parallel, CA-125 is a commonly used ovarian tumor marker. This study aimed to compare the roles of GLS and CA-125 in distinguishing between benign and malignant ovarian tumors. The research was conducted as a comparative study, enrolling 156 patients with ovarian tumors. Preoperative serum CA-125 and GLS levels were analyzed to evaluate their effectiveness in distinguishing between benign and malignant ovarian tumors. The results revealed that the mean levels of CA-125 and GLS were significantly higher in malignant ovarian tumors compared to benign ones (389.54±494.320 vs. 193.15±529.932 and 17.37±12.156 vs. 7.48±4.095), respectively. The CA-125 and GLS cut-off point of 108.2 and 18.32, respectively, were associated with malignant ovarian tumor. Multivariate analyses showed that GLS had higher predictive capabilities compared to CA-125 (OR 9.4 vs. 2.1). The accuracy of using GLS combined with CA-125 was higher than using CA-125 alone (73.1% vs 68.8.%). Higher levels of CA-125 and GLS are associated with malignant ovarian tumors. In conclusion, GLS outperforms CA-125 in distinguishing between benign and malignant ovarian tumors. The combination of GLS and CA-125 had better accuracy in distinguishing benign and malignant ovarian tumor when compared to using CA-125 alone.
    DOI:  https://doi.org/10.1111/cts.13603
  5. J Pharm Biomed Anal. 2023 Jul 27. pii: S0731-7085(23)00374-6. [Epub ahead of print]235 115605
    Mapping metabolic perturbations induced by glutathione activatable synthetic ion channels in human breast cancer cells.
    Saleem Yousf, Javid A Malla, Devika M Sardesai, Shilpy Sharma, Pinaki Talukdar, Jeetender Chugh.
      Ion channels and transporters play key roles in various biological processes, including cell proliferation and programmed cell death. Recently, we reported that 2,4-dinitrobenzene-sulfonyl-protected N1,N3-dihexy-2-hydroxyisophthalamide (1) forms ion channels upon activation by glutathione (GSH) and results in the induction of apoptosis by depleting the intracellular GSH reservoir in cancer cells. However, the detailed molecular events leading to the induction of apoptosis by these synthetic transport systems in cancer cells still need to be uncovered. Along these lines, we investigated the alterations in cellular metabolites and the associated metabolic pathways by performing untargeted global metabolic profiling of breast cancer cells - MCF-7 - using 1H NMR-based metabolomics. The evaluation of spectral profiles from MCF-7 cells exposed to 1 and their comparison with those corresponding to untreated (control) cells identified 14 significantly perturbed signature metabolites. These metabolites belonged mostly to antioxidant defence, energy metabolism, amino acid biosynthesis, and lipid metabolism pathways and included GSH, o-phosphocholine, malate, and aspartate, to name a few. These results would help us gain deeper insights into the molecular mechanism underlying 1-mediated cytotoxicity of MCF-7 cells and eventually help identify potential novel therapeutic targets for more effective cancer management.
    Keywords:  Cancer; Glutathione; Ion Channels; Metabolites; NMR
    DOI:  https://doi.org/10.1016/j.jpba.2023.115605
  6. Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00910-5. [Epub ahead of print]42(8): 112899
    Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.
    Manabu Kodama, Gouji Toyokawa, Osamu Sugahara, Shigeaki Sugiyama, Naoki Haratake, Yuichi Yamada, Reona Wada, Shinkichi Takamori, Mototsugu Shimokawa, Tomoyoshi Takenaka, Tetsuzo Tagawa, Hiroki Kittaka, Takeshi Tsuruda, Kentaro Tanaka, Yushiro Komatsu, Keisuke Nakata, Yuri Imado, Koji Yamazaki, Isamu Okamoto, Yoshinao Oda, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyuki Shimizu, Tomoharu Yoshizumi, Keiichi I Nakayama.
      Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.
    Keywords:  CP: Cancer; HPRT1; host glutamine metabolism; nucleotide biosynthesis; salvage pathway; small cell lung cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.112899
  7. Matrix Biol. 2023 Aug 02. pii: S0945-053X(23)00082-3. [Epub ahead of print]
    SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation.
    Xinru Xue, Xi Zeng, Xiaoqian Wu, Kexin Mu, Yue Dai, Zhifeng Wei.
      Intestinal fibrosis is a prevalent complication of Crohn's disease (CD), characterized by excessive deposition of extracellular matrix (ECM), and no approved drugs are currently available for its treatment. Sirtuin 4 (SIRT4), a potent anti-fibrosis factor in mitochondria, has an unclear role in intestinal fibrosis. In this study, fibroblasts isolated from biopsies of stenotic ileal mucosa in CD patients were analyzed to identify the most down-regulated protein among SIRT1-7, and SIRT4 was found to be the most affected. Moreover, in in vivo and in vitro models of intestinal fibrosis, SIRT4 expression was significantly decreased in a TGF-β dependent manner, and its decrease was negatively associated with disease severity. SIRT4 impeded ECM deposition by inhibiting glutaminolysis, but not glycolysis, and α-ketoglutarate (α-KG) was identified as the key metabolite. Specifically, SIRT4 hinders SIRT5's stabilizing interaction with glutaminase 1 (GLS1), thereby facilitating the degradation of GLS1. KDM6, rather than KDM4, is a potential mediator for α-KG-induced transcription of ECM components, and SIRT4 enhances the enrichment of H3K27 on their promotors and enhancers. These findings indicate that the activation of TGF-β signals decreases the expression of SIRT4 in intestinal fibrosis, and SIRT4 can facilitate GLS1 degradation, thereby resisting glutaminolysis and alleviating intestinal fibrosis, providing a novel therapeutic target for intestinal fibrosis.
    Keywords:  SIRT4; extracellular matrix deposition; glutaminase 1; glutaminolysis; intestinal fibrosis
    DOI:  https://doi.org/10.1016/j.matbio.2023.08.001
  8. Front Biosci (Landmark Ed). 2023 07 21. 28(7): 143
    Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.
    Giovanni Tossetta, Sonia Fantone, Daniela Marzioni, Roberta Mazzucchelli.
      Prostate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells.
    Keywords:  KEAP; NRF2; antioxidants; chemotherapy; modulator; prostate cancer; signaling
    DOI:  https://doi.org/10.31083/j.fbl2807143
  9. Nat Cancer. 2023 Aug 03.
    Cancer cell plasticity during tumor progression, metastasis and response to therapy.
    Andrea Pérez-González, Kevin Bévant, Cédric Blanpain.
      Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
    DOI:  https://doi.org/10.1038/s43018-023-00595-y
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