Inhibition of arachidonate lipoxygenase12 targets lung cancer through inhibiting EMT and suppressing RhoA and NF-κB activity

Chen, Junwen; Tong, Wei; Liao, Mingxin; Chen, Dengyi

doi:10.1016/j.bbrc.2020.01.166

Cited by 12 publications

(11 citation statements)

References 21 publications

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“…Alox12 overexpression has been reported in lung, gastric and breast cancers. [29][30][31] Our work supports and further extends the previous findings that apart from cancer committed cells, Alox12-12-HETE axis is also upregulated in primary cancer stem cells, and furthermore that this axis is mediated by oncogenic stress (eg, the presence of BCR-ABL) in cancer. Alox12 elevation has been shown to be positively associated with an advanced stage and poor differentiation in prostate cancer.…”

Section: Discussionsupporting

confidence: 88%

“…This data adds to the recent evidence supporting the important role of Alox12-12-HETE in the growth and survival of cancer. [29][30][31]33,34 Notably, we find that Alox12 inhibition impairs CML HSPCs functions (Figure 3). This finding is consistent with the previous reports on the other two ALOX family members that loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia in mice, 35 and Alox15 is required for chronic myeloid leukemia stem cell survival, 15 suggesting the important roles of ALOX family in leukemia stem cells.…”

Section: Discussionmentioning

confidence: 75%

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<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

Si¹,

Hu²,

Yong³

2020

CMAR

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Introduction: Chronic myeloid leukemia (CML) is a myeloid malignancy characterized by the oncogene BCR-ABL. CML responds well to therapy targeting BCR-ABL in the chronic phase but is resistant to treatment when it progresses to the blast phase (BP). This study attempted to address whether arachidonate 12-lipoxygenase (Alox12) confers to CML drug resistance. Materials and Methods: We analyzed the expression of Alox12 using Western blotting, ELISA, and RT-PCR methods. Loss of functional analysis was performed using cellular activity assays on CML and normal hematopoietic stem/progenitor cells (HSPCs). Results: Alox12 and 12-Hydroxyeicosatetraenoic acid (12-HETE) are overexpressed in BP-CML but not HSPCs, and that Alox12-12-HETE axis is regulated by BCR-ABL. The Alox12-12-HETE axis is required for CML. Specific Alox12 inhibitor inhibits colony formation, survival, and self-renewal capacity in BP-CML HSPCs, and to a significantly greater extent than in normal HSPCs. Of note, the Alox12 inhibitor significantly augments dasatinib's efficacy in BP-CML HSPCs. Mechanism studies show that Alox12 inhibition does not affect activities of essential signaling pathways involved in maintaining stem cell function, such as Wnt, p53, and bone morphogenetic protein (BMP). In contrast, we show that Alox12 inhibition disrupts nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis and induces oxidative stress and damage in CML HSPCs and committed cells. Conclusion: Alox12-12-HETE axis is a specific and critical regulator of BP-CML HSPCs functions. Pharmacological inhibition of Alox12 may be useful in BP-CML.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 75%

<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

Si¹,

Hu²,

Yong³

2020

CMAR

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“…Yang et al found that ALOX12 was downregulated in recurrence of hepatocellular carcinoma and regulated the ALOX12–12HETE–GPR31 signaling pathway ( Yang et al, 2019 ). In lung cancer, overexpression of ALOX12 facilitated cell growth and migration by promoting RhoA and NF-κB activity ( Chen et al, 2020 ). ALOX12B protein, another isoform of arachidonic acid 12-lipoxygenase, mainly catalyzes arachidonic acid to 12R-hydroxyeicosatetraenoic acid ( Zheng et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

Song

Yan-hu

Gao

et al. 2021

Front. Mol. Biosci.

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Esophageal squamous cell carcinoma (ESCC) accounts for the main esophageal cancer (ESCA) type, which is also associated with the greatest malignant grade and low survival rates worldwide. Ferroptosis is recently discovered as a kind of programmed cell death, which is indicated in various reports to be involved in the regulation of tumor biological behaviors. This work focused on the comprehensive evaluation of the association between ferroptosis-related gene (FRG) expression profiles and prognosis in ESCC patients based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). ALOX12, ALOX12B, ANGPTL7, DRD4, MAPK9, SLC38A1, and ZNF419 were selected to develop a novel ferroptosis-related gene signature for GEO and TCGA cohorts. The prognostic risk model exactly classified patients who had diverse survival outcomes. In addition, this study identified the ferroptosis-related signature as a factor to independently predict the risk of ESCC. Thereafter, we also constructed the prognosis nomogram by incorporating clinical factors and risk score, and the calibration plots illustrated good prognostic performance. Moreover, the association of the risk score with immune checkpoints was observed. Collectively, the proposed ferroptosis-related gene signature in our study is effective and has a potential clinical application to predict the prognosis of ESCC.

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“…A. R. Lourenco et al [14] con rmed that the signi cant contribution of the EMT pathway in BRCA metastasis. J. Chen et al [15] reported that arachidonate lipoxygenase12 could suppress growth and migration of lung cancer cells by suppressing EMT pathway activity. Besides, some other studies have also noted that the activation of the EMT pathway was positively correlated with cancer metastasis, such as colorectal cancer [16] cervical cancer [17,18] and prostate cancer [19].…”

Section: Discussionmentioning

confidence: 99%

GABRQ is Overexpressed and Correlated with Tumor Progression in Breast Cancer

Mei

Cui

Zheng

et al. 2021

Preprint

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Background: Breast cancer (BRCA) is the most common type of women's cancer with a high incidence. The function of gamma-aminobutyric acid A receptor θ subunit (GABRQ) has been studied in other cancers. The results demonstrated that the expression levels of GABRQ were closely associated with tumor prognosis. However, the functions and mechanisms of GABRQ in BRCA remain unclear.Materials and methods: We used the public genome datasets and a tissue microarray (TMA) cohort to analyze the GABRQ expression levels. We performed Immunohistochemistry (IHC) and Western blot to determine GABRQ expression in BRCA cell lines and tissues. Cell proliferation was assessed by EDU assay and colony formation assay. Transwell assay was carried out to investigate the cell invasion ability in vitro and Xenograft nude mouse model was constructed to test the function of GABRQ on tumor growth in vivo. Moreover, we utilized bioinformatic analysis to identify the potential molecular mechanisms mediated by GABRQ modification in BRCA.Results: GABRQ was markedly up-regulated in BRCA tissues, and the expression levels of GABRQ were closely associated with BRCA prognosis. Functional analysis elucidated that knockdown of GABRQ could suppress BRCA cell growth and invasion in vitro, and inhibit tumor development in vivo. Moreover, we found that GABRQ overexpression activated the EMT signaling pathway.Conclusions: These results demonstrated that the function of GABRQ in BRCA progression provided potential prognostic predictors for BRCA patients.

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Inhibition of arachidonate lipoxygenase12 targets lung cancer through inhibiting EMT and suppressing RhoA and NF-κB activity

Cited by 12 publications

References 21 publications

<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

A Novel Ferroptosis-Related Biomarker Signature to Predict Overall Survival of Esophageal Squamous Cell Carcinoma

GABRQ is Overexpressed and Correlated with Tumor Progression in Breast Cancer

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