Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes

Park, Bohye; Kim, Ji Yeon; Riffey, Olivia F.; Dowker-Key, Presley; Bruckbauer, Antje; McLoughlin, James M.; Bettaieb, Ahmed; Donohoe, Dallas R.

doi:10.1038/s41598-022-12827-9

Cited by 11 publications

(3 citation statements)

References 38 publications

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“…SLC2A1 - related reaction is up-regulated and RRM2, PKM and SIRT6 -related reactions are down-regulated while NT5E -related reactions show the same pattern in the case of breast cancer. The metabolic pattern that SLC2A1 is up-regulated in colorectal cancer well recapitulates the previous experimental study showing SLC2A1 is highly expressed in colorectal cancer patients [30] and the down-regulation pattern of PKM is also supported by the study describing that the PKM1 , an isoform of PKM is decreased in human colorectal carcinomas as compared to non-cancerous tissue [31].…”

Section: Resultssupporting

confidence: 85%

Learning the Relationship Between Variants, Metabolic Fluxes and Phenotypes

Kim,

Han,

Nam

et al. 2024

Preprint

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In the dynamic field of cancer research, the fusion of genetics and machine learning presents a groundbreaking opportunity to understand the intricate links between genomic variations and cancer phenotypes. Despite the wealth of genetic data, translating it into actionable insights remains a challenge, particularly in the context of complex cellular metabolism. VaMP (Variants,Metabolic Fluxes &Phenotypes), our novel approach, addresses this by integrating neural networks and metabolic models, offering a comprehensive framework for deciphering cancer biology. The developed method leverages a novel end-to-end neural network architecture, integrating genome-scale metabolic models (GSMs) to capture the intricate relationship between genetic variations and cellular phenotypes. VaMP’s encoder maps genetic variants to metabolic fluxes through a series of carefully designed steps utilizing neural network and GSM, while the decoder predicts phenotype probabilities using the differences between input and reference fluxes. The training data comprise mutation information and phenotypes, eliminating the need for explicit metabolic flux data preparation. Validation experiments on five cancer types demonstrate VaMP’s ability to identify significant genes and metabolic signatures. Further utilizing SCREENER and co-occurrence analyses, the assessment reveals VaMP’s capacity to anticipate established gene-disease relationships. The identified metabolic signatures are robustly substantiated by diverse literature grounded in experimental studies. Furthermore, an in-depth exploration of the outcomes from five VaMP models involved the correlation analysis for variants and fluxes to establish connections between significant genes and cancer-causing variants. Overall, VaMP can be used as a promising tool for unraveling the complex interplay between genetic alterations and cancer phenotypes, with implications for understanding disease mechanisms and identifying novel therapeutic targets.

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Section: Resultssupporting

confidence: 85%

Learning the Relationship Between Variants, Metabolic Fluxes and Phenotypes

Kim,

Han,

Nam

et al. 2024

Preprint

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“…The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. And data suggest that the decrease in PKM1 expression may contribute to the upregulation of glycolysis and the downregulation of butyrate oxidation in CRC cells ( 253 ). Furthermore, multiple studies have suggested that PTBP1 ( 254 ), lncRNA SNHG6 ( 255 ), lncRNA HOXB-AS3 ( 256 ), Sam68 ( 257 ), MicroRNA-124 ( 258 ), LncRNA XIST/miR-137 axis ( 259 ), TRIM29 ( 260 ), and other molecules can target PKM1/PKM2 and influence their ratio, thereby impacting the growth, glycolysis, and even chemoresistance of CRC cells.…”

Section: Tumor-associated Splicing Variants In Crc: From Roles To Pot...mentioning

confidence: 99%

Targeted splicing therapy: new strategies for colorectal cancer

Zheng,

Zhong,

et al. 2023

Front. Oncol.

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RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.

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“…Quite different from or even contrary to this study, utilizing a transgenic mouse model of prostate cancer, Davidson et al (2022) chiefly evaluated the role of PKM1 in terms of tumor growth, demonstrating that PKM1 hinders the development of prostate cancer. Metabolically, another report (Park et al, 2022) demonstrated that PKM1 inhibits glycolysis and hypoxia‐inducible factor‐1 alpha (HIF‐1α). Reflected from these scattered evidence available, the function of PKM1 implicated in tumor growth is still controversial and appears to be tissue specific.…”

Section: Low Level Of Concern About Pkm1mentioning

confidence: 99%

Positioning determines function: Wandering PKM2 performs different roles in tumor cells

He,

Liang,

Tan

et al. 2023

Cell Biology International

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Short for pyruvate kinase M2 subtype, PKM2 can be said of all‐round player that is notoriously known for its metabolic involvement in glycolysis. Holding a dural role as a metabolic or non‐metabolic (kinase) enzyme, PKM2 has drawn extensive attention over its biological roles implicated in tumor cells, including proliferation, migration, invasion, metabolism, and so on. wandering PKM2 can be transboundary both intracellularly and extracellularly. Specifically, PKM2 can be nuclear, cytoplasmic, mitochondrial, exosomal, or even circulate within the body. Importantly, PKM2 can function as an RNA‐binding protein (RBP) to self‐support its metabolic function. Despite extensive investigations or reviews available surrounding the biological roles of PKM2 from different angles in tumor cells, little has been described regarding some novel role of PKM2 that has been recently found, including, for example, acting as RNA‐binding protein, protection of Golgi apparatus, and remodeling of microenvironment, and so forth. Given these findings, in this review, we summarize the recent advancements made in PKM2 research, mainly from non‐metabolic respects. By the way, PKM1, another paralog of PKM2, seems to have been overlooked or under‐investigated since its discovery. Some recent discoveries made about PKM1 are also preliminarily mentioned and discussed.

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Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes

Cited by 11 publications

References 38 publications

Learning the Relationship Between Variants, Metabolic Fluxes and Phenotypes

Learning the Relationship Between Variants, Metabolic Fluxes and Phenotypes

Targeted splicing therapy: new strategies for colorectal cancer

Positioning determines function: Wandering PKM2 performs different roles in tumor cells

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