In vivo genetic dissection of tumor growth and the Warburg effect

Wang, Chengwei; Purkayastha, Arunima; Jones, Kevin T.; Thaker, Shivani K.; Banerjee, Utpal

doi:10.7554/elife.18126

Cited by 90 publications

(133 citation statements)

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“…ROS use a positive feedback loop to strengthen the upstream members of the glycolytic pathway, which is the key point in the metabolic reprogramming of cancer tissues, not only in the absence of sufficient oxygen tensions. Even though hypoxia stabilizes HIF-1α, in the metabolic reprogramming of the cell, hypoxia, unlike HIF-1α, does not play an important role [145]. Interestingly in this study, although Pvr activation was linked to many tumor phenotypes, such as cell shape changes, overproliferation, aerobic glycolysis and local migration, it did not possess any metastatic capability, which correlated with no loss of the cell epithelial polarity that leads to invasive and metastatic abilities [193].…”

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 81%

“…Since Pvr is an RTK, the authors asked if other activated RTKs that lead to overproliferation may also cause increased LDH activity. Interestingly, they found that, unlike Pvr act , InR act and Egfr act did not induce any LDH expression [145]. Sima, one of the key inducers of LDH in tumors [189], was assessed next, and it was found that Sima protein was stabilized in a Pvr act background and its overexpression led to LDH-induced activity [145].…”

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

“…Peroxidasin (Pxn), a general antioxidant, reduced ROS activity, and when it was expressed together with Pvr act led to the deactivation of the JNK pathway (previously active in a Pvr act background), the suppression of Sima protein accumulation and the reduction of LDH activity. Thus, ROS have a crucial role in metabolism regulation [145]. Moreover, ROS are the central players in the metabolic profile of the cell [191].…”

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

“…In addition, the transcription factor HIF-1α controls expression of a number of genes involved in different hallmarks of cancer including modifiers of cellular metabolism that facilitate neoplasia [189]. A recent study in Drosophila investigated the mechanisms impinging on metabolism deregulation under sufficient oxygen levels and the role of HIF-1α in this process [145] (Figure 3). The authors induced a glycolytic tumor in the fly wing imaginal disk by expressing an activated form of the PDGF/VEGF-receptor (Pvr) oncogene, and they observed whether various oncogenic signaling pathways can interact with HIF-1α/sima and successively upregulate key metabolic enzymes [145].…”

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

“…A recent study in Drosophila investigated the mechanisms impinging on metabolism deregulation under sufficient oxygen levels and the role of HIF-1α in this process [145] (Figure 3). The authors induced a glycolytic tumor in the fly wing imaginal disk by expressing an activated form of the PDGF/VEGF-receptor (Pvr) oncogene, and they observed whether various oncogenic signaling pathways can interact with HIF-1α/sima and successively upregulate key metabolic enzymes [145]. Pvr was found to induce strong lactate dehydrogenase (LDH) enzymatic activity, which is a hallmark of aerobic glycolysis and the Warburg effect.…”

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

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The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

Tamamouna¹,

Pitsouli²

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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The hypoxia-inducible factor-1α (HIF-1α) is an evolutionarily conserved transcription factor with prominent roles in the hypoxic response, cell survival, angiogenesis and cancer. HIF-1α functions as a sensor of molecular oxygen: in the presence of oxygen, it is degraded by the proteasome, whereas in reduced oxygen tensions, it heterodimerizes with the constitutively expressed HIF-1b subunit forming the functional HIF1 transcription factor, which enters the nucleus to control expression of hypoxia-inducible genes. Since HIF-1α has been found upregulated in several cancers, it has attracted a lot of clinical interest, because it represents an interesting candidate for pharmacological chemotherapy interventions. In this chapter, we discuss our current knowledge on the HIF1 transcription factors and their major roles in development, physiology, angiogenesis and cancer using examples of recent studies in the model organism Drosophila melanogaster. Given the striking functional conservation between the mammalian and fruit fly HIF-1α, we expect that future studies in the Drosophila model will not only expand our knowledge on the basic HIF1 biology, but they will also pinpoint conserved molecular regulators of HIF1 that might lead to the discovery of novel cancer therapeutics.Keywords: hypoxia, tumorigenesis, Warburg effect, metabolism, tracheogenesis, inflammation, Drosophila 1. HIF-1α in mammalian angiogenesis, inflammation and cancer Oxygen is required for survival of all animalsOxygen (O 2 ) is the main ingredient of the atmospheric air and is required for the survival of all living organisms. It is also present in the seas and oceans, and it is necessary for survival of all aquatic living organisms. Oxygen accumulated on Earth's atmosphere about 2.5 billion © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.years ago [1]. However, it was discovered only 245 years ago, by the chemist Carl Wilhelm Scheele [2]. Its main role in the survival of animals derives from its utilization during cellular respiration. Specifically, oxygen is involved in oxidative phosphorylation, the process that transfers the chemical energy stored in carbon bonds to the phosphate bonds of Adenosine Tri-Phosphate (ATP), which is the main energy carrier in all cell types of living organisms [3]. In addition, oxygen is the main component of ATP production, because it is the final electron acceptor of the respiratory chain. Oxygen-electron reaction leads to the release of reactive oxygen species (ROS), which, when accumulated, results in oxidative stress and eventually cell death [4,5]. Oxygen is necessary as an energy substrate, and the danger of oxidative damage needs to be kept at equilibrium. Therefore, oxygen homeostasis is critical for all cellular processes, and its intermittent supply resul...

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Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 81%

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

Section: Hif-1α/sima In Drosophila Tumorigenesismentioning

confidence: 99%

See 3 more Smart Citations

The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

Tamamouna¹,

Pitsouli²

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Metabolic Recoding of NSUN2‐Mediated m⁵C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m⁵C‐ENO1 Positive Feedback Loop

Chen,

Deng,

Hong

et al. 2024

Advanced Science

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The RNA modification, 5‐methylcytosine (m5C), has recently gained prominence as a pivotal post‐transcriptional regulator of gene expression, intricately intertwined with various tumorigenic processes. However, the exact mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain unclear. Here, it is determined that the m5C methyltransferase NSUN2 exhibits significantly elevated expression and exerts an oncogenic function in CRC. Mechanistically, NSUN2 and YBX1 are identified as the “writer” and “reader” of ENO1, culminating in the reprogramming of the glucose metabolism and increased production of lactic acid in an m5C‐dependent manner. The accumulation of lactic acid derived from CRC cells, in turn, activates the transcription of NSUN2 through histone H3K18 lactylation (H3K18la), and induces the lactylation of NSUN2 at the Lys356 residue (K356), which is crucial for capturing target RNAs. Together, these findings reveal an intriguing positive feedback loop involving the NSUN2/YBX1/m5C‐ENO1 signaling axis, thereby bridging the connection between metabolic reprogramming and epigenetic remodeling, which may shed light on the therapeutic potential of combining an NSUN2 inhibitor with immunotherapy for CRC.

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FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming

Zhang

Yang

Chai

et al. 2019

Intl Journal of Cancer

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The role of Fyn‐related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK‐KO‐H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial–mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK‐KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U‐13C flux assay revealed that FRK‐KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.

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In vivo genetic dissection of tumor growth and the Warburg effect

Cited by 90 publications

References 113 publications

The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

Metabolic Recoding of NSUN2‐Mediated m⁵C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m⁵C‐ENO1 Positive Feedback Loop

FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming

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In vivo genetic dissection of tumor growth and the Warburg effect

Cited by 90 publications

References 113 publications

The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

The Hypoxia-Inducible Factor-1α in Angiogenesis and Cancer: Insights from the Drosophila Model

Metabolic Recoding of NSUN2‐Mediated m5C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m5C‐ENO1 Positive Feedback Loop

FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming

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Metabolic Recoding of NSUN2‐Mediated m⁵C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m⁵C‐ENO1 Positive Feedback Loop