Altered metabolism in cancer: insights into energy pathways and therapeutic targets

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Сен. 18, 2024

Язык: Английский

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Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy

Acta Pharmacologica Sinica, Год журнала: 2024, Номер 45(8), С. 1533 - 1555

Опубликована: Апрель 15, 2024

Язык: Английский

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Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle

Cancer Letters, Год журнала: 2024, Номер 585, С. 216661 - 216661

Опубликована: Фев. 2, 2024

Inhibitory immune checkpoint (ICP) molecules are pivotal in inhibiting innate and acquired antitumor responses, a mechanism frequently exploited by cancer cells to evade host immunity. These evasion strategies contribute the complexity of progression therapeutic resistance. For this reason, ICP have become targets for drugs, particularly monoclonal antibodies, collectively referred as inhibitors (ICI), that counteract such cancer-associated suppression restore responses. Over last decade, however, it has clear tumor cell-associated ICPs can also induce cell-intrinsic effects, particular epithelial-mesenchymal transition (EMT) macroautophagy (hereafter autophagy). Both these processes profound implications metastasis drug responsiveness. This article reviews positive or negative cross-talk undergo with autophagy EMT. We discuss upregulated response same stimuli Moreover, themselves, when overexpressed, an EMT-inducing stimulus. As regards autophagy, been shown either stimulate inhibit while itself up- downregulate expression ICPs. dynamic equilibrium extends autophagy-apoptosis axis, further emphasizing complexities cellular Eventually, we delve into intricate balance between apoptosis, elucidating its role broader interplay dynamics influenced In final part article, speculate about driving forces underlying contradictory outcomes reciprocal, inhibitory, stimulatory effects ICPs, EMT, autophagy. A conclusive identification may allow achieve improved using combinations ICIs compounds acting on EMT and/or Prospectively, translate increased broadened efficacy compared what is currently achieved ICI-based clinical protocols.

Язык: Английский

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Construction of nitroreductase-responsive near-infrared composite nanoprobe and its application in tumor hypoxia imaging

Talanta, Год журнала: 2025, Номер 289, С. 127750 - 127750

Опубликована: Фев. 14, 2025

Язык: Английский

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An in- vitro measurement for the toxicity of peptides inhibit hexokinase II in breast cancer cell lines

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 27, 2025

The role of the enzyme hexokinase 2 in many cancers has been identified through increased glycolysis or binding to pro-apoptotic channel located outer mitochondrial membrane, (VDCA1) and protein kinase (MTOR). To prevent cancer-causing pathways this enzyme, it is possible disrupt interaction subunits. Peptides can be utilized interfere with subunits by amino acids that contribute dimerization. Nowadays, peptides have become a suitable option for treatment various diseases, especially cancer, due their small size, ease synthesis, ability penetrate tumor. This study examined toxic effect inhibit on tumorigenic MCF-7 MDA-MB-231 non-tumorigenic MCF10A cell lines MTT analysis flow cytometry determine apoptosis. line experienced significant decrease proliferation both peptides. RYALFSS peptide caused number cells, but EKGLGATTHPTAAVKML increase. There was no increase line. study's finding indicate serve as tool carcinogenic cells.

Язык: Английский

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The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities

Neoplasia, Год журнала: 2024, Номер 58, С. 101076 - 101076

Опубликована: Окт. 31, 2024

Язык: Английский

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A comprehensive pan-cancer analysis identifies a novel glycolysis score and its hub genes as prognostic and immunological biomarkers

Translational Cancer Research, Год журнала: 2023, Номер 12(10), С. 2852 - 2874

Опубликована: Окт. 1, 2023

Background: Glycolysis plays significant roles in tumor progression and immune response. However, the exact role of glycolysis prognosis regulation has not been explored all cancer types. This study first calculated a novel score screened out 12 glycolytic hub genes, comprehensively analyzed molecular expression, clinical implications, features among pan-cancer. Methods: The was derived by single sample gene set enrichment analysis (ssGSEA) algorithm. correlations with parameters were using “limma” package. Downstream pathways identified Gene Set Enrichment Analysis (GSEA). cell infiltration validated three databases. association between some immunotherapy biomarkers Pearson correlation analysis. Single-nucleotide variation (SNV), copy number (CNV), DNA methylation, drug sensitivity analyses genes investigated. IMvigor210 GSE91061 immunotherapeutic cohorts retrieved to assess ability predict efficacy. expression key detected normal endometrial lines. Results: We found that generally higher tissues compared high predominated as risk prognostic factor. A associated decreased immunostimulatory natural killer (NK) cells CD8+ T infiltration, well increased immunosuppressive M2-tumor-associated macrophages (M2-TAM) infiltration. Tumor mutational burden (TMB), microsatellite instability (MSI), checkpoints (ICPs) closely interacted frequency mutation confirmed be colon adenocarcinoma (COAD) patients score. SNV, CNV, methylation occurred at different frequencies showed impacts on survival outcomes. predictive value for outcomes two cohorts. levels differ Conclusions: work indicated correlated an microenvironment. They could served promising aiding diagnosis, predicting response patients.

Язык: Английский

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mTORC2‐AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells

The FASEB Journal, Год журнала: 2024, Номер 38(5)

Опубликована: Март 7, 2024

Abstract Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem and cancer, its regulatory mechanisms are still being updated. Here, we found previously unappreciated mechanism of mammalian target rapamycin complex 2 (mTORC2) in regulating intestinal cell maintenance cancer progression. mTORC2 key subunits expression levels kinase activity were specifically upregulated cells, mouse tumors, human colorectal (CRC) tissues. Genetic ablation scaffolding protein Rictor both models lines revealed that played an important role promoting proliferation self‐renewal. Moreover, utilizing organoid culture, loss function was shown to impair growth gut adenoma tumor organoids. Based on these findings, performed RNA‐seq noticed significant metabolic reprogramming conditional knockout mice. Among all the pathways, carbohydrate metabolism most profoundly altered, further studies demonstrated promoted epithelial cells. Most importantly, showed rate‐limiting enzyme glycolysis, 6‐phosphofructo‐2‐kinase (PFKFB2), direct mTORC2‐AKT signaling. PFKFB2 phosphorylated upon activation, but not mTORC1, this process AKT‐dependent. Together, study identified novel underlying activated offering potential therapeutic targets treating CRC.

Язык: Английский

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Metabolic Reprogramming by Mutant GNAS Creates an Actionable Dependency in Intraductal Papillary Mucinous Neoplasms of the Pancreas

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 15, 2024

ABSTRACT Objective Oncogenic “hotspot” mutations of KRAS and GNAS are two major driver alterations in Intraductal Papillary Mucinous Neoplasms (IPMNs), which bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D Gnas R201C co-expression p48 Cre ; LSL-G12D Rosa26 LSL-rtTA Tg (TetO- ) mice (“ Kras;Gnas ” mice) caused development cystic lesions recapitulating IPMNs. Here, we aim unveil the consequences mutant expression on phenotype, transcriptomic profile, genomic dependencies. Design performed multimodal transcriptional profiling (bulk RNA sequencing, single cell spatial transcriptomics) “ Kras;Gnas” autochthonous model tumor-derived lines ( cells), where is inducible. A genome-wide CRISPR/ Cas 9 screen was conducted identify potential vulnerabilities ;Gnas co-expressing cells. Results Induction – resulting G (s) alpha signaling leads emergence a gene signature gastric (pyloric type) metaplasia neoplastic epithelial CRISPR screening identified synthetic essentiality glycolysis-related genes Gpi1 Slc2a1 Real-time metabolic analyses cells confirmed enhanced glycolysis upon induction. made expressing more dependent for their survival. Protein kinase A-dependent phosphorylation glycolytic intermediate enzyme PFKFB3 increased Conclusion Multiple orthogonal approaches demonstrate results pyloric dependency during IPMN pathogenesis. The observed reprogramming may provide target therapeutics interception SUMMARY What already known this topic Activating found majority (IPMNs). Expression drives IPMN-like murine pancreas eventually progress adenocarcinoma (PDAC). study adds Mutant aberrant IPMNs with mucin production. Aberrant enhances via protein PFKFB3. Enhanced KRAS;GNAS -mutated validated multiple vitro vivo represents an actionable vulnerability. How might affect research, practice or policy present provides mechanistic insight into how alters biology -mutant neoplasia through metaplastic reprogramming. Targeting represent both therapeutic avenue as well opportunity intercepting progression invasive cancer.

Язык: Английский

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Genomic Deletion of PFKFB3 Decreases In Vivo Tumorigenesis

Cancers, Год журнала: 2024, Номер 16(13), С. 2330 - 2330

Опубликована: Июнь 26, 2024

Rapidly proliferative processes in mammalian tissues including tumorigenesis and embryogenesis rely on the glycolytic pathway for energy biosynthetic precursors. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) plays an important regulatory role glycolysis by activating key rate-limiting enzyme, 6-phosphofructo-1-kinase (PFK-1). We have previously determined that decreased PFKFB3 expression reduced growth transformed cells vitro suppressed xenograft vivo. In earlier studies, we created a constitutive knockout mouse to interrogate function of vivo but failed generate homozygous offspring due requirement embryogenesis. now developed novel transgenic model exhibits inducible pan-tissue Pfkfb3 gene deletion (Pfkfb3fl/fl). induced genomic these mice found it effectively activity. To evaluate functional consequences vivo, crossed Cre-bearing Pfkfb3fl/fl with oncogene-driven tumor models markedly their glucose uptake growth. summary, our studies reveal critical characterize effective powerful further investigation its multiple biological processes.

Язык: Английский

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