Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway

Yu, Liang; Hou, Lidan; Li, Linjing; Li, Lei; Zhu, Liming; Wang, Yu; Huang, Xin; Hou, Yichao; Zhu, Da‐Yuan; Zou, Huimin; Gu, Yu; Weng, Xiaoling; Wang, Yingying; Li, Yue; Wu, Tianqi; Yao, Mengfei; Groß, Isabelle; Gaiddon, Christian; Luo, Meng; Wang, Jianhua; Meng, Xiangjun

doi:10.1038/s41388-019-1035-8

Cited by 93 publications

(79 citation statements)

References 59 publications

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“…Among them, 3 miRNAs including mmu‐miR‐129‐1‐3p, ‐200b, and ‐149‐3p are conserved between humans and mice. MicroRNA‐200b has been well studied as an epithelial‐mesenchymal transition‐related miRNA and miR‐149‐3p has been reported to be involved in some types of cancers, whereas the role of miR‐129‐1‐3p has not been clearly elucidated. Thus, we focused on miR‐129‐1‐3p.…”

Section: Resultsmentioning

confidence: 99%

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

et al. 2020

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MicroRNAs (miRNAs) fine-tune cellular signaling by regulating expression of signaling proteins, and aberrant expression of miRNAs is observed in many cancers. The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. In previous investigations of miRNA-mediated control of c-Src-related oncogenic pathways, we identified miRNAs that were downregulated in association with c-Src transformation and uncovered the signaling networks by predicting their target genes, which might act cooperatively to control tumor progression. Here, to further elucidate the process of cell transformation driven by c-Src, we analyzed the expression profiles of miRNAs in a doxycycline-inducible Src expression system. We found that miRNA (miR)-129-1-3p was downregulated in the early phase of c-Src-induced cell transformation, and that reexpression of miR-129-1-3p disrupted c-Src-induced cell transformation. In addition, miR-129-1-3p downregulation was tightly associated with tumor progression in human colon cancer cells/tissues. Expression of miR-129-1-3p in human colon cancer cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified c-Src and its critical substrate Fer, and c-Yes, a member of the Src family of kinases, as novel targets of miR-129-1-3p. Furthermore, we found that miR-129-1-3p-mediated regulation of c-Src/Fer and c-Yes is important for controlling cell adhesion and invasion. Downregulation of miR-129-1-3p by early activation of c-Src increases expression of these target genes and synergistically promotes c-Src-related oncogenic signaling. Thus, c-Src-miR-129-1-3p circuits serve as critical triggers for tumor progression in many human cancers that harbor upregulation of c-Src. K E Y W O R D Scolon cancer, malignancy, microRNA, signaling, Src | 419 OKUZAKI et Al.

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Section: Resultsmentioning

confidence: 99%

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

et al. 2020

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“…DCA binds to PDK and attenuates the inhibition of PDH activity, which shifts metabolism from glycolysis to OXPHOS, with subsequent increase of ROS production, decrease of mitochondrial membrane potential, efflux of pro-apoptotic mediators from the mitochondria, and induction of mitochondria-dependent apoptosis [45]. Interestingly, some authors have recently shown that DCA restored colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway [46]. Accordingly, it was also reported that the antitumor activity of DCA was dependent on a functional p53 status, exhibiting synergistic growth inhibitory effects in combination with the p53 activator Nutlin-3 [47].…”

Section: Discussionmentioning

confidence: 99%

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

Ramos

Calheiros

Almeida

et al. 2020

IJMS

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The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.

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“…Upon adding DCA to EGFR TKIs, the inhibition of glycolysis is fatal for the developing tumor. Interestingly, a recently published study shows that DCA also increases the expression of the key tumor suppressor p53 in colorectal cancer, highlighting new possible anticancer mechanisms induced by DCA [95].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Dyrstad¹,

Lotsberg²,

Tan³

et al. 2020

Preprint

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Background Non-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted therapy. Drug resistance is an example of cancer cell plasticity where cells change according to diverse microenvironmental pressure, which can be described as a way of evolution by natural selection. Metabolic rewiring during cancer development may support several malignant features and facilitate emergence of therapy resistant clones. Results Analysis of transcriptome data from two independent NSLSC patient cohorts identified upregulated markers of glucose metabolism and ROS defense in tumors compared to normal tissue. We show that these alterations were associated with increased expression of pyruvate dehydrogenase kinase 1 (PDK1). We established relevant in vitro models to study metabolic alterations in the context of resistance to EGFR TKIs to determine if targeted metabolic intervention would prevent development of resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC cells. The PDK inhibitor dichloroacetate (DCA) was shown to reduce cell growth. This mechanism was associated with redirected metabolism towards pyruvate and lactate oxidation, and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Conclusion We propose that the intracellular stress created by redirecting pyruvate metabolism can prevent EGFR TKI resistance in NSCLC.

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Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway

Cited by 93 publications

References 59 publications

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

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