Journal: Oncology Research

Article Title: Branched-Chain Amino Acid Metabolic Reprogramming and Cancer: Molecular Mechanisms, Immune Regulation, and Precision Targeting

doi: 10.32604/or.2025.071152

Figure Lengend Snippet: Molecular mechanisms and pathways of branched-chain amino acid (BCAA) metabolic reprogramming in cancer cells. BCAAs (leucine, isoleucine, valine) are transported into cancer cells mainly by LAT1 (encoded by SLC7A5). Intracellular BCAAs undergo transamination by branched-chain amino acid transaminases (BCAT1 cytosolic; BCAT2 mitochondrial), generating branched-chain α-keto acids (BCKAs) and glutamate. Subsequently, BCKAs are oxidized by branched-chain α-keto acid dehydrogenase (BCKDH), regulated by kinase BCKDK and phosphatase PPM1K, producing acetyl-CoA and intermediates for the tricarboxylic acid (TCA) cycle. BCAA metabolism intersects key signaling pathways such as PI3K/AKT/mTORC1, affecting histone modifications (DOT1L, P300), epigenetic regulation (TET2), DNA damage responses (RNF8/RAD51), lipogenesis (ACLY/FASN), oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) generation, and redox homeostasis (glutathione, GSH). Dysregulated BCAA metabolism thus contributes to tumor promotion, therapy resistance, oxidative stress tolerance, immune cell infiltration, and ferroptosis regulation. Therapeutic agents targeting LAT1 (JPH203), BCAT1 (WQQ345/EB), BCKDK (BT2), and mTORC1 (Rapamycin) are highlighted. LAT1, L-type amino acid transporter 1; BCAA, branched-chain amino acid; BCAT, branched-chain amino acid transaminase; BCKA, branched-chain α-keto acid; BCKDH; branched-chain α-keto acid dehydrogenase, BCKDK, branched-chain α-keto acid dehydrogenase kinase; PPM1K, protein phosphatase Mg 2+ /Mn 2+ -dependent 1K; TCA, tricarboxylic acid; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTORC1, mechanistic target of rapamycin complex 1; DOT1L, disruptor of telomeric silencing 1-like; TET2, ten-eleven translocation methylcytosine dioxygenase 2; RNF8, ring finger protein 8; OXPHOS, oxidative phosphorylation; ETC, electron transport chain, ROS, reactive oxygen species; GSH, glutathione; α-KG, α-ketoglutarate

Article Snippet: Researchers at GlaxoSmithKline recently developed potent and selective BCAT2 inhibitors based on a 2-aryl benzimidazole scaffold [ ].

Techniques: Protein-Protein interactions, Phospho-proteomics, Translocation Assay

Journal: Oncology Research

Article Title: Branched-Chain Amino Acid Metabolic Reprogramming and Cancer: Molecular Mechanisms, Immune Regulation, and Precision Targeting

doi: 10.32604/or.2025.071152

Figure Lengend Snippet: BCAA metabolic reprogramming fuels growth and multi-modal therapy resistance and highlights actionable nodes. Cancer cells increase leucine/isoleucine/valine uptake through LAT1 and channel BCAAs through BCAT1 (cytosol) and BCAT2 (mitochondria) to generate branched-chain α-ketoacids (BCKAs), acetyl-CoA and TCA-cycle intermediates. These fluxes sustain ATP production and mTORC1 signaling (activated downstream of PI3K–AKT and growth factors), which drives protein and lipid synthesis (via ACLY) and glycolysis, promoting survival under stress. Transamination also produces glutamate, replenishing α-ketoglutarate and glutathione (GSH) to buffer ROS, suppress ferroptosis, and blunt cytotoxic chemotherapy/radiation injury. In targeted-therapy settings, oncogenic programs (e.g., EGFR mutation) and acquired upregulation of BCAT1 maintain metabolic signaling and epigenetic states that support resistance to TKIs. Tumor-intrinsic amino-acid consumption further reshapes the microenvironment and can undermine antitumor immunity. Pharmacologic interventions indicated in red—JPH203 (LAT1 blockade), WQQ-345 or eupalinolide B (EB) (BCAT1 inhibition), and rapamycin (mTORC1 inhibition)—interrupt these circuits, decreasing anabolic supply lines, dampening mTORC1 output, restoring redox vulnerability, and thereby resensitizing tumors to chemo-, targeted-, and immunotherapies. BCAAs, Branched-chain amino acids (leucine, isoleucine, valine); LAT1, L-type amino acid transporter 1; BCAT1/BCAT2, Branched-chain amino acid transaminase 1/2; BCKAs, Branched-chain α-ketoacids; α-KG, Alpha-ketoglutarate; TCA cycle, Tricarboxylic acid cycle; ACLY, ATP-citrate lyase; GLS, Glutaminase; PI3K, Phosphoinositide 3-kinase; AKT, Protein kinase B; mTORC1, Mechanistic (mammalian) target of rapamycin complex 1; ROS, Reactive oxygen species; GSH, Glutathione; RC: Respiratory chain (electron transport chain); EGFR, Epidermal growth factor receptor; NSCLC, Non-small cell lung cancer; TKIs, Tyrosine kinase inhibitors; IDH, Isocitrate dehydrogenase; Acetyl-CoA, Acetyl coenzyme A; JPH203, Selective LAT1 inhibitor; WQQ-345/EB, BCAT1 inhibitors (WQQ-345; eupalinolide B); Rapamycin, mTORC1 inhibitor

Article Snippet: Researchers at GlaxoSmithKline recently developed potent and selective BCAT2 inhibitors based on a 2-aryl benzimidazole scaffold [ ].

Techniques: Mutagenesis, Inhibition

Journal: The FASEB Journal

Article Title: Pyruvate prevents the onset of the cachectic features and metabolic alterations in myotubes downregulating STAT3 signaling

doi: 10.1096/fj.202200848r

Figure Lengend Snippet: FIGURE 5 Myotubes treated with the MPC inhibitor UK5099 acquire cachectic features. Myotubes have been treated with UK5099 (10 μM final) for 24 h. (A) Representative images of control and UK5099-treated myotubes. (B) Myotube width obtained by ImageJ and calculated in at least 10 randomly chosen fields. (C) Ubiquitin immunoblot. (D) LC3II immunoblot. In (C) and (D) the bar graph reports the mean value of each sample obtained by the ratio with the PVDF membrane used for normalization. (E) Lactate assay. (F) Oxygen consumption rate (OCR). (G) Analysis of mitochondrial membrane potential by confocal microscopy. Mitochondria are stained with TMRM probe (red fluorescence), while blue fluorescence shows the nuclei. The bar graph reports the mean value of fluorescence for each sample measured using ImageJ software in at least 10 randomly chosen fields. (H) PDH activity. C, control myotubes. n = 3; *p < .05.

Article Snippet: Unless otherwise specified, all used reagents were obtained from Sigma- Aldrich, Inc. (St. Louis, MO, USA); SDS- PAGE materials and ECL detection reagents were purchased from Bio- Rad Laboratories, (Hercules, USA); anti- Fbx32/ Atrogin1 (ab168372), anti- OXPHOS (ab110413), antiSTAT3 (ab68153), and anti- Myosin Heavy Chain (MHC) (ab 91506) primary antibodies were from Abcam (Cambridge, UK); anti- PDH- E1 (sc- 377092) and anti- ubiquitin (sc8017) primary antibodies, mitochondrial pyruvate carrier (MPC) inhibitor UK5099 (sc- 361394) and STAT3 inhibitor WP1066 (sc- 203282) were from Santa Cruz Biotechnology (Dallas, TX, USA); anti- LC3B (#3868) and anti- phosphoTyr705- STAT3 (#9145) primary antibodies were from Cell Signaling Technology Inc. (Danvers, MA,USA); Tetramethyl- rhodamine methyl ester (TMRM) probe was from Molecular Probe (Eugene, OR, USA); K- LATE kit for lactate assay was from Megazyme (Bray, Ireland); pyridine and N- tert- Butyldimethylsilyl- N- methyltrifluoroacetamide with 1% tert- Butyldimethylchlorosilane (MBTSTFA + 1% TBDMCS) were from Pierce, ThermoFisher Scientific (Waltham, MA, USA).

Techniques: Control, Ubiquitin Proteomics, Western Blot, Membrane, Lactate Assay, Confocal Microscopy, Staining, Fluorescence, Software, Activity Assay