Integrated analysis of scRNA-seq and bulk RNA-seq data identifies BHLHE40 as a key gene in pancreatic cancer progression and gemcitabine resistance DOI
Yang Wu, Chun Zhang, Jiayi Huang

и другие.

Seminars in Oncology, Год журнала: 2025, Номер 52(2), С. 152338 - 152338

Опубликована: Апрель 1, 2025

Язык: Английский

AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer DOI
Changfeng Li, Yuanda Liu, Chang Liu

и другие.

Science Translational Medicine, Год журнала: 2025, Номер 17(783)

Опубликована: Янв. 29, 2025

Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is highly selective and first-in-class inhibitor under clinical development. Here, we report that advanced glycosylation end product-specific receptor (AGER) plays key role in mediating resistance PDAC cells. The up-regulation AGER within cancer cells instigates macropinocytosis, facilitating internalization serum albumin subsequent amino acid generation. These acids are then used to synthesize antioxidant glutathione, leading due inhibition apoptosis. underlying molecular mechanism involves AGER's interaction with diaphanous-related formin 1 (DIAPH1), protein responsible for driving Rac family small GTPase (RAC1)-dependent macropinosome formation. effectiveness safety combining pharmacological inhibitors AGER-DIAPH1 complex (using RAGE299) or macropinocytosis EIPA) were confirmed patient-derived xenografts, orthotopic models, genetically engineered mouse models. This combination therapy also induces high-mobility group box (HMGB1) release, resulting antitumor CD8+ T cell response immunocompetent mice. Collectively, study findings underscore potential enhance efficacy blockade targeting AGER-dependent macropinocytosis.

Язык: Английский

Процитировано

3
CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer DOI Creative Commons
Fangquan Chen, Hu Tang, Changfeng Li

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 7, 2025

Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent death. We reveal CYP51A1, gene involved cholesterol synthesis, as key suppressor of alkalization-induced pancreatic cancer cells. Inducing intracellular alkalization by small molecule JTC801 leads decrease endoplasmic reticulum levels, subsequently activating SREBF2, transcription factor responsible for controlling expression genes biosynthesis. Specifically, SREBF2-driven upregulation CYP51A1 prevents accumulation within lysosomes, leading TMEM175-dependent lysosomal proton efflux, ultimately resulting inhibition In animal models, including xenografts, syngeneic orthotopic, patient-derived genetic or pharmacological enhances effectiveness suppressing tumors. These findings demonstrate role CYP51A1-dependent pathway inhibiting highlight its potential targetable vulnerability cancer. Previously, opioid analgesic JCT801 was reported induce via disruption authors investigate JCT801-induced death, identifying synthesis gene,

Язык: Английский

Процитировано

1
NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism DOI Creative Commons
Jiao Liu, Hu Tang, Fangquan Chen

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Ноя. 28, 2024

Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), major non-protein thiol in cells, acts as cuproptosis inhibitor pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits chelating copper, contrasting its role blocking ferroptosis inhibiting lipid peroxidation. The classical inducer, ES-Cu (elesclomol plus copper), increases protein stability transcription factor NFE2L2 (also known NRF2), leading to upregulation gene expression glutamate-cysteine ligase modifier subunit (GCLM) catalytic (GCLC). GCLM GCLC are rate-limiting enzymes synthesis, increased transported into mitochondria via solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression culture mouse models. These findings not only reveal distinct mechanisms ferroptosis, but also suggest potential combination strategy suppress PDAC growth.

Язык: Английский

Процитировано

5
KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC DOI Creative Commons
Xiangyan Jiang, Tao Wang, Bin Zhao

и другие.

Cell Reports Medicine, Год журнала: 2025, Номер 6(2), С. 101966 - 101966

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Glutathione Metabolism in Ferroptosis and Cancer Therapy DOI
Xiangfei Xue, Manyuan Wang,

Jiangtao Cui

и другие.

Cancer Letters, Год журнала: 2025, Номер unknown, С. 217697 - 217697

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Integrated analysis of scRNA-seq and bulk RNA-seq data identifies BHLHE40 as a key gene in pancreatic cancer progression and gemcitabine resistance DOI
Yang Wu, Chun Zhang, Jiayi Huang

и другие.

Seminars in Oncology, Год журнала: 2025, Номер 52(2), С. 152338 - 152338

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0