Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma

Cancer Research, Год журнала: 2022, Номер 82(19), С. 3516 - 3531

Опубликована: Окт. 4, 2022

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both nonmetabolic functions. Further elucidation of role in EGFR inhibitor resistance metastasis, two leading causes death lung adenocarcinoma, could help improve patient outcomes. Here, we found aberrant upregulation phosphoserine aminotransferase 1 (PSAT1) confers erlotinib tumor metastasis adenocarcinoma. Depletion PSAT1 restored sensitivity to synergistically augmented tumoricidal effect. Mechanistically, inhibition activated ROS-dependent JNK/c-Jun pathway induce cell apoptosis. In addition, interacted with IQGAP1, subsequently activating STAT3-mediated migration independent its activity. Clinical analyses showed expression positively correlated human Collectively, these findings reveal multifunctionality promoting malignancy through activities.Metabolic functions confer promote suggesting therapeutic targeting may attenuate malignant features cancer.

Язык: Английский

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Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Окт. 24, 2022

Abstract Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary model, we find enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes hydroxylation free acids (FAs), enriched subpopulation ESCC with high metastatic potential, FA2H knockdown markedly mitigates lesions. Moreover, increased expression positively associated poor survival patients ESCC. Lipidomics analysis identifies two dihydroceramides—Cer(d18:0/24:0) Cer(d18:0/24:1)—are FA2H-depleted metastasizing cells. Upon administration, Cer(d18:0/24:0) Cer(d18:0/24:1) impair formation overt metastases mouse experimental model. Then, forkhead box protein C2 (FOXC2) are found be co-upregulated populations specimens, further experimentally verified transcriptionally induced by FOXC2, boosted per se tumour necrosis factor α (TNFα), critical pro-metastasis cytokine microenvironment, Together, these results demonstrate TNFα-FOXC2-FA2H novel signaling axis promote metastasis, its downstream dihydroceramide products could promising drugs intervene metastasis.

Язык: Английский

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CD8+ T cell metabolic rewiring defined by scRNA-seq identifies a critical role of ASNS expression dynamics in T cell differentiation

Cell Reports, Год журнала: 2022, Номер 41(7), С. 111639 - 111639

Опубликована: Ноя. 1, 2022

T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8+ activated and differentiated in vitro physiological medium resolve these metabolic dynamics. identify a differential time-dependent reliance of activating on the synthesis versus uptake various non-essential amino acids, which we corroborate with functional assays. also genes that potentially dictate outcome cell differentiation, by ranking them based expression Among them, find asparagine synthetase (Asns), whose peaks for effector decays toward memory formation. Disrupting dynamics ASNS overexpression promotes phenotype, enhancing anti-tumor response adoptively transferred mouse melanoma model. thus provide resource dynamic changes activation as modulator differentiation.

Язык: Английский

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GLUT3 promotes macrophage signaling and function via RAS-mediated endocytosis in atopic dermatitis and wound healing

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(21)

Опубликована: Сен. 18, 2023

The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that expression increased after M1 polarization stimuli found M2 stimulation macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired bone marrow-derived Alternatively activated macrophages from the skin patients with atopic dermatitis showed expression, a calcipotriol-induced model was rescued LysM-Cre Glut3fl/fl mice. M2-like human wound tissues as assessed by transcriptomics costaining, significantly decreased nonhealing, compared healing, diabetic foot ulcers. In an excisional healing model, mice macrophage delayed healing. promoted IL-4/STAT6 signaling, independently its glucose transport activity. Unlike plasma membrane-localized GLUT1, localized primarily to endosomes required for efficient endocytosis IL-4Rα subunits. interacted directly GTP-bound RAS vitro vivo through intracytoplasmic loop domain, this interaction STAT6 activation polarization. PAK macropinocytosis were also without GLUT3, suggesting broader roles regulation endocytosis. Thus, is alternative function, transport-independent, RAS-mediated role activation.

Язык: Английский

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Obesity and renal cell carcinoma: Biological mechanisms and perspectives

Seminars in Cancer Biology, Год журнала: 2023, Номер 94, С. 21 - 33

Опубликована: Июнь 5, 2023

Язык: Английский

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