Apelin-mediated deamidation modification of HMGA1 promotes tumorigenesis by enhancing SRBEP1 activity and Lipid Synthesis

Abstract Apelin is a ligand of the G protein-coupled receptor that promotes tumor growth in malignant cancers. However, the molecular mechanisms through which apelin promotes tumorigenesis are unknown. Here, we confirmed that apelin promotes tumorigenesis in lung cancer cells by increasing the synthesis of fatty acids, which induces abnormal lipid metabolism. Apelin interacts with high-mobility group A HMGA1 and mediates sterol-regulatory-element-binding protein 1 (SREBP1) activity, which is required for lung tumorigenesis and lipid metabolism. Deamidation modification of HMGA1 is regulated by apelin enhanced SRBEP1 activity and lipid synthesis. Moreover, deamidated HMGA1 can enhance the formation of the apelin-HMGA1-SREBP1 complexes and increases SREBP1 activity, which induces abnormal lipid metabolism. As an energy regulator, Apelin forms a multi-protein complexes with HMGA1 to increase of lung cancer cells viability. Our results indicate that apelin is important in lipid metabolism and cancer cell proliferation.

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Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

Cancer Biomarkers ◽

10.3233/cbm-210189 ◽

2021 ◽

pp. 1-9

Author(s):

Huan Guo ◽

Baozhen Zeng ◽

Liqiong Wang ◽

Chunlei Ge ◽

Xianglin Zuo ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Lung Cancer Cells ◽

Invasion And Migration ◽

And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

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PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer

Cell Transplantation ◽

10.1177/09636897211001772 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110017

Author(s):

Jianhao Huang ◽

Yonghua Zheng ◽

Xiao Zheng ◽

Bao Qian ◽

Qi Yin ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Human Lung ◽

Akt Signaling ◽

Lung Cancer Cells ◽

Signaling Cascades ◽

Human Lung Cancer ◽

Mesenchymal Transition ◽

Human Lung Cancer Cells

The type II protein arginine methyltransferase 5 (PRMT5) has been engaged in various human cancer development and progression types. Nevertheless, few studies uncover the biological functions of PRMT5 in the epithelial-mesenchymal transition (EMT) of human lung cancer cells, and the associated molecular mechanisms and signaling cascades are entirely unknown. Here, we show that PRMT5 is the ectopic expression in human lung cancer tissues and cell lines. Further study reveals that silencing PRMT5 by lentivirus-mediated shRNA or blocking of PRMT5 by specific inhibitor GSK591 attenuates the expression levels of EMT-related markers in vivo, using the xenograft mouse model. Moreover, our results show that down-regulation of PRMT5 impairs EGFR/Akt signaling cascades in human lung cancer cells, whereas re-expression of PRMT5 recovers those changes, suggesting that PRMT5 regulates EMT probably through EGFR/Akt signaling axis. Altogether, our results demonstrate that PRMT5 serves as a critical oncogenic regulator and promotes EMT in human lung cancer cells. More importantly, our findings also suggest that PRMT5 may be a potential therapeutic candidate for the treatment of human lung cancer.

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SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180523104541 ◽

2018 ◽

Vol 18 (6) ◽

pp. 484-493 ◽

Cited By ~ 29

Author(s):

Xiang Cheng ◽

Jianying Li ◽

Deliang Guo

Keyword(s):

Lipid Metabolism ◽

Cancer Therapy ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Regulatory Element ◽

Lipid Synthesis ◽

Feedback Regulation ◽

Negative Feedback Regulation ◽

Expression Of Genes ◽

New Findings

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

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Abstract 3738: IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells

10.1158/1538-7445.am2016-3738 ◽

2016 ◽

Author(s):

Janani Panneerselvam ◽

Akhil Srivastava ◽

Ranganayaki Muralidharan ◽

Qi Wang ◽

Wei Zheng ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

High Mobility ◽

Akt Signaling ◽

High Mobility Group ◽

Lung Cancer Cells

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Enhancement of Cisplatin Sensitivity in High Mobility Group 2 cDNA-transfected Human Lung Cancer Cells

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1999.tb00673.x ◽

1999 ◽

Vol 90 (1) ◽

pp. 108-115 ◽

Cited By ~ 16

Author(s):

Hitoshi Arioka ◽

Kazuto Nishio ◽

Tomoyuki Ishida ◽

Hisaoh Fukumoto ◽

Kazuya Fukuoka ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Human Lung ◽

High Mobility ◽

High Mobility Group ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Human Lung Cancer Cells ◽

Cisplatin Sensitivity ◽

Group 2

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Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568009619666190325144636 ◽

2019 ◽

Vol 19 (10) ◽

pp. 838-851 ◽

Cited By ~ 2

Author(s):

Augustine T. Nkembo ◽

Felix Amissah ◽

Elizabeth Ntantie ◽

Rosemary A. Poku ◽

Olufisayo O. Salako ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

A549 Cells ◽

Fold Increase ◽

Lung Cancer Cells ◽

Ras Signaling ◽

Extrinsic Pathway ◽

Lung Cancers ◽

Protein Levels

Background: Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. Objective: In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. Methods: The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined. Results: Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2). Conclusion: Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.

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