Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect

Zhang, Meng; Liu, Tingting; Sun, Hui‐Chuan; Weng, Wei-Hung; Zhang, Qiongyan; Liu, Chenchen; Han, Yang; Sheng, Weiqi

doi:10.1111/cas.13562

Cited by 47 publications

(43 citation statements)

References 38 publications

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“…This finding was further supported by the MeRIP assay, RNA stabilization assay, and qRT-PCR in control and METTL3-knockout or METTL3-knockdown CRC cells. Our data and previous studies [38,39] demonstrate that HK2 and SLC2A1 may act as oncogenes to promote cell glycolysis metabolism. Here, we also firstly reveal that HK2 and GLUT1 participate in METTL3-mediated biological function in CRC.…”

Section: Discussionsupporting

confidence: 81%

“…HK2 and SLC2A1 (GLUT1) are functionally essential target genes of METTL3 in CRC Hexokinase 2 (HK2) is a pivotal kinase in the glycolytic pathway [37]. Previous studies have demonstrated that HK2 activity is remarkably increased in various malignant neoplasms, as well as in CRC [38,39]. Glucose transporter 1 (GLUT1), encoded by SLC2A1, is the predominant glucose transporter expressed on colonic epithelial cells [40].…”

Section: Transcriptome-wide M 6 A-seq and Rna-seq Assays Identified Pmentioning

confidence: 99%

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m6A-dependent glycolysis enhances colorectal cancer progression

et al. 2020

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Background: Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6methyladenosine (m 6 A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m 6 A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m 6 A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Methods: Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m 6 A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. Results: A strong correlation between METTL3 and 18 F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3'UTR regions of HK2, and the 3'UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M 6 A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m 6 A reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions: METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m 6 A-IGF2BP2/3-dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.

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Section: Discussionsupporting

confidence: 81%

Section: Transcriptome-wide M 6 A-seq and Rna-seq Assays Identified Pmentioning

confidence: 99%

m6A-dependent glycolysis enhances colorectal cancer progression

et al. 2020

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“…Several studies have shown that PIM1 is an essential oncogene role in many cancers, which was consistent with its functional role in GBC. For example, Brasó-Maristany et al reported that PIM1 could regulate cell death and tumor growth in hepatocellular carcinoma, 10 colorectal cancer, 22 and triple-negative breast cancer. 23 Similar results were observed in clear-cell renal-cell carcinoma 24 and salivary adenoid cystic carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Zhang et al reported that PIM1 expression was notably overexpressed in response to glucose deprivation-induced metabolic stress through AMP-activated protein kinase signal. 22 Leung et al reported that knockdown of PIM1 could reduce glucose consumption and decrease key enzymes of the glycolytic pathway in hepatocellular carcinoma. 10 Taken together, glycolysis may play an important role in enhancing GBC progression, and PIM1 may promote tumor growth by reprogramming glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of PIM1 regulates glycolysis and suppresses tumor progression in gallbladder cancer

Xue¹,

He²,

Hu³

et al. 2018

CMAR

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BackgroundPIM1, a serine/threonine kinase, plays an essential role in tumorigenesis of multiple types of tumors. However, the expression pattern and functions of PIM1 in gallbladder cancer (GBC) remain largely unknown.Materials and methodsImmunohistochemistry, quantitative real-time PCR, and western blot analysis were performed to measure the expression of PIM1. Tissue microarray analysis was used to confirm the relationship between PIM1 expression and clinical outcomes of GBC patients. Finally, in vivo and in vitro functional studies were performed to detect the inhibition of PIM1 by RNAi or specific inhibitor in GBC cells.ResultsWe observed that PIM1 was dramatically overexpressed in GBC tissues, and its expression levels were positively related with clinical malignancies and a poor prognosis. Inhibition of PIM1 via RNAi or enzyme-specific inhibitor could suppress GBC cell proliferation, migration, and invasion both in vitro and vivo. Additionally, flow cytometry assays and cell cycle assays indicated that PIM1 inhibition promoted cell apoptosis and induced cell cycle arrest. Remarkably, inhibition of PIM1 could drive a metabolic shift from aerobic glycolysis to oxidative phosphorylation. We found that inhibition of PIM1 mechanistically reduced glucose consumption by regulating key molecules in aerobic glycolysis.ConclusionPIM1 may serve as an oncogene in GBC and be involved in the regulation of glycolysis. PIM1 is a promising therapeutic target for the treatment of human GBC.

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“…Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase, involved in cell cycle progression, cell growth, cell survival and therapy resistance. PIM-1 is activated in various types of cancer, amongst which prostate [14][15][16] , colorectal [15,[17][18][19] , triple negative breast cancer (TNBC) [20,21] , hematologic malignancies [22][23][24] , neuroblastoma [25] and lung cancer [26] . For this reason, PIM kinases could provide a common target for the treatment of diverse malignancies.…”

Section: Introductionmentioning

confidence: 99%

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Bracht¹,

Karachaliou²,

Berenguer³

et al. 2019

JCMT

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Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

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Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect

Cited by 47 publications

References 38 publications

m6A-dependent glycolysis enhances colorectal cancer progression

m6A-dependent glycolysis enhances colorectal cancer progression

Downregulation of PIM1 regulates glycolysis and suppresses tumor progression in gallbladder cancer

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

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