Glutamine's Role in Cancer Cell Survival

𝐃𝐄𝐂𝐈𝐏𝐇𝐄𝐑𝐈𝐍𝐆 𝐆𝐋𝐔𝐓𝐀𝐌𝐈𝐍𝐄 𝐀𝐃𝐃𝐈𝐂𝐓𝐈𝐎𝐍 𝐈𝐍 𝐂𝐀𝐍𝐂𝐄𝐑 𝐂𝐄𝐋𝐋𝐒: 𝐁𝐑𝐈𝐃𝐆𝐈𝐍𝐆 𝐎𝐍𝐂𝐎𝐆𝐄𝐍𝐄 𝐑𝐄𝐆𝐔𝐋𝐀𝐓𝐈𝐎𝐍 𝐖𝐈𝐓𝐇 𝐈𝐍𝐍𝐎𝐕𝐀𝐓𝐈𝐕𝐄 𝐓𝐇𝐄𝐑𝐀𝐏𝐄𝐔𝐓𝐈𝐂 𝐒𝐓𝐑𝐀𝐓𝐄𝐆𝐈𝐄𝐒 The intricate relationship between cancer cell metabolism and glutamine has been a focal point of research, leading to groundbreaking insights. The review article "Glutamine Addiction in Tumor Cell: Oncogene Regulation and Clinical Treatment" by Xian Li, Xueqiang Peng, Yan Li, and their team, published in Cell Communication and Signaling, 2024, offers a comprehensive exploration into this domain. Their work delves into how tumor cells undergo metabolic reprogramming, elevating their glutamine consumption to support rapid proliferation. This phenomenon, known as glutamine addiction, opens new avenues for targeted cancer therapies. 𝑫𝒆𝒄𝒐𝒅𝒊𝒏𝒈 𝑮𝒍𝒖𝒕𝒂𝒎𝒊𝒏𝒆 𝑴𝒆𝒕𝒂𝒃𝒐𝒍𝒊𝒔𝒎: 𝑻𝒉𝒆 𝑷𝒂𝒕𝒉𝒘𝒂𝒚 𝒕𝒐 𝑷𝒐𝒕𝒆𝒏𝒕𝒊𝒂𝒍 𝑻𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕𝒔 Glutamine's pivotal role in cancer cell growth and survival stems from its contribution to biosynthetic processes, including amino acid, fatty acid, and nucleotide production. By manipulating the metabolic pathway of glutamine, the review underscores potential therapeutic targets, highlighting the influence of oncogenes like C-MYC, KRAS, HIF, and p53 on glutamine metabolism regulation. 𝑻𝒂𝒓𝒈𝒆𝒕𝒊𝒏𝒈 𝑮𝒍𝒖𝒕𝒂𝒎𝒊𝒏𝒆 𝒊𝒏 𝑪𝒂𝒏𝒄𝒆𝒓 𝑻𝒉𝒆𝒓𝒂𝒑𝒚: 𝑨 𝑷𝒓𝒐𝒎𝒊𝒔𝒊𝒏𝒈 𝑯𝒐𝒓𝒊𝒛𝒐𝒏 The review sheds light on the latest developments in targeting glutamine metabolism as a cancer treatment strategy. It discusses various inhibitors and their stages of research, emphasizing the importance of identifying tumor cells' glutamine dependency for effective therapeutic intervention. The insights from Li and colleagues' work suggest a promising future where targeting glutamine metabolism could become a cornerstone in cancer treatment, offering hope for more precise and effective therapies. 𝑪𝒉𝒂𝒍𝒍𝒆𝒏𝒈𝒆𝒔 𝒂𝒏𝒅 𝑶𝒑𝒑𝒐𝒓𝒕𝒖𝒏𝒊𝒕𝒊𝒆𝒔 𝒊𝒏 𝑮𝒍𝒖𝒕𝒂𝒎𝒊𝒏𝒆-𝑻𝒂𝒓𝒈𝒆𝒕𝒆𝒅 𝑪𝒂𝒏𝒄𝒆𝒓 𝑻𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕 Despite the promising prospects, challenges such as tumor cell heterogeneity and compensatory metabolic pathways persist. The review calls for innovative approaches to overcome these hurdles, including the identification of novel biomarkers and the development of drugs with improved specificity and reduced toxicity. 𝑪𝒐𝒏𝒄𝒍𝒖𝒔𝒊𝒐𝒏: 𝑨 𝑺𝒕𝒆𝒑 𝑭𝒐𝒓𝒘𝒂𝒓𝒅 𝒊𝒏 𝑪𝒂𝒏𝒄𝒆𝒓 𝑴𝒆𝒕𝒂𝒃𝒐𝒍𝒊𝒔𝒎 𝑹𝒆𝒔𝒆𝒂𝒓𝒄𝒉 As the field moves towards more targeted and individualized treatments, the insights from this comprehensive review highlight the potential of targeting glutamine metabolism in the fight against cancer, marking a significant advancement in oncological research and therapeutic strategies. 𝑭𝒐𝒐𝒅 𝒇𝒐𝒓 𝑻𝒉𝒐𝒖𝒈𝒉𝒕: What unknown interactions between glutamine metabolism and oncogene regulation could redefine cancer therapy?

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Nature: Communications Biology. 29 May 2019 Purna Mukherjee, Zachary M. Augur, Mingyi Li, Collin Hill, Bennett Greenwood, Marek A. Domin, Gramoz Kondakci, Niven R. Narain, Michael A. Kiebish, Roderick T. Bronson, Gabriel Arismendi-Morillo, Christos Chinopoulos & Thomas N. Seyfried Abstract: Glioblastoma (GBM) is an aggressive primary human brain tumor that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumor cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management. Purna Mukherjee, Zachary M. Augur, Mingyi Li, Collin Hill, Bennett Greenwood, Marek A. Domin, Gramoz Kondakci, Niven R. Narain, Michael A. Kiebish, Roderick T. Bronson, Gabriel Arismendi-Morillo, Christos Chinopoulos & Thomas N. Seyfried Full text of the article enclosed https://lnkd.in/eCxFhPMG

Targeting pancreatic cancer glutamine dependency confers vulnerability to #GPX4-dependent ferroptosis:- •Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC’s response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy. #highlights:- •Prolonged Gln restriction or DON treatment induces ferroptosis program in PDAC. •CRISPR-Cas9 identifies Paxip1 mediating H3K4me3 upregulation under glutamine restriction. •Paxip1 promotes transcription activation of Hmox1 and Gpx4 via H3K4me3. •DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis.