Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling

Wang, Zi Li; Fan, Zhi Qiang; Jiang, Han; Qu, Jie

doi:10.1093/carcin/bgs367

Cited by 63 publications

(49 citation statements)

References 37 publications

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“…A certain portion of NSCLC patients can not benefit from NSAIDs, and they still suffer from rapid progression of tumor in clinical practice. Studies have confirmed that Celecoxib can promote epithelial-mesenchymal transition (EMT) of cancer cells, leading to increased metastatic risk [17]. Taken together, COX-2/HIF-1α signaling was probably not the only IL-1β downstream pathway to promote cancer.…”

Section: Discussionmentioning

confidence: 99%

IL-1β-Mediated Up-Regulation of WT1D via miR-144-3p and Their Synergistic Effect with NF-κB/COX-2/HIF-1α Pathway on Cell Proliferation in LUAD

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: IL-1β is an important mediator of “inflammation-cancer" transformation through IL-1β/NF-κB/COX-2/HIF-1α signaling pathway, whereas certain portion of patients with lung adenocarcinoma (LUAD) still suffer from rapid tumor progression in clinical practice, indicating the occurrence of potential bypass. Methods: Real-time polymerase chain reaction was applied to examine the expressions of mir-144-3p, WT1, NF-κB, COX2 and HIF-1α at the mRNA level in 127 LUAD samples and corresponding adjacent tissues. miR-144-3p mimic and antagormiR were used to trigger activation and suppression of miR-144-3p in A549 cells, respectively. MTT assay and Western blotting analysis were carried out to evaluate the cell proliferation. Stable clones with over-expression or knockdown of WT1 were generated with plasmid or shRNA by lentiviral vector technology in H1568 and H1650 NSCLC cell lines, respectively. Dual luciferase reporter assay was performed to validate the effect of miR-144-3p on WT1D. Xenograft model was established for in vivo experiment, and TCGA data were extracted for validation. Results: miR-144-3p could suppress the WT1D expression at the post-transcriptional level, hence regulating cell proliferation in LUAD. WT1 and COX-2 were independent prognostic factors of LUAD patients. In addition, inhibition of IL-1β/miR-144-3p/WT1D and IL-1β/NF-κB/COX-2/HIF-1α pathways using miR-144-3p mimic and Celecoxib, respectively, displayed synergistic suppressive effect on cell proliferation in LUAD. Conclusion: A de novo IL-1β/miR-144-3p/WT1D axis was involved in proliferative regulation of LUAD. Moreover, simultaneous blockade of both IL-1β/miR-144-3p/WT1D and IL-1β/NF-κB/COX-2/ HIF-1α pathways might have synergistic suppressive effect on cell proliferation in LUAD.

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Section: Discussionmentioning

confidence: 99%

IL-1β-Mediated Up-Regulation of WT1D via miR-144-3p and Their Synergistic Effect with NF-κB/COX-2/HIF-1α Pathway on Cell Proliferation in LUAD

Zhang

et al. 2018

Cell Physiol Biochem

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“…In tumor tissues, DDR2 overexpression is often positively correlated with Vimentin and negatively with E-cadherin (19,20). DDR2 overexpression in tumor cells has previously been demonstrated to be sufficient in inducing morphological changes, and promoting enhanced migration and invasion, which are essential biological processes in tumor metastasis (23,25). The increased migration and invasion capacity are dependent on the secretion of matrix metalloproteinases (MMP) (26,27).…”

Section: Discussionmentioning

confidence: 99%

DDR2 facilitates papillary thyroid carcinoma epithelial mesenchymal transition by activating ERK2/Snail1 pathway

et al. 2017

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Abstract. The upregulation of discoidin domain receptor tyrosine kinase 2 (DDR2) has been reported to be associated with poor prognosis and metastasis in numerous tumor types by inducing epithelial-mesenchymal transition (EMT); however, the expression profile of DDR2 in papillary thyroid carcinoma (PTC) with local metastasis and the effect of DDR2 on PTC cells remain unknown. The aim of the present study was to investigate the expression levels of DDR2 in tumor tissues of patients with PTC with local metastasis and cell lines and to determine the effect of DDR2 on EMT in PTC cells. In the present study, it was demonstrated that DDR2 was significantly increased in tumor tissues of patients with PTC with local metastasis and human PTC cell lines. The overexpression of DDR2 by lentiviral transfection decreased E-cadherin protein, increased Vimentin protein, and promoted cell migration and invasion. The inhibition of DDR2 reversed transforming growth factor-β-and collagen I-induced EMT. EMT induced by DDR2 overexpression was suggested to be dependent on increased Snail1 protein level following extracellular signal-regulated kinase (ERK)2 activation. The inhibition of Snail1 or ERK2 was sufficient to abrogate DDR2-induced PTC cell EMT. In conclusion, these results indicate that DDR2 is upregulated in PTC tissues with local metastasis. Overexpression of DDR2 induced EMT in PTC cells by activating ERK2 and stabilizing Snail1, making it a promising therapeutic target for reducing PTC local or distant metastasis.

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“…Therefore, it is hypothesized that, by inhibiting COX-2, the COX-1 pathway may become dominant in normal cells, thereby assisting tumor growth in COX-2-negative cells. Other investigators reported that celecoxib treatment induced epithelial-to-mesenchymal transition, which promoted cell invasion and rendered cells resistant to chemotherapy (28). These negative effects may obscure the positive effects in COX-2-expressing patients.…”

Section: Grade ------------------------------------------------------mentioning

confidence: 99%

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

Yokouchi

Kanazawa

Ishida

et al. 2014

Molecular and Clinical Oncology

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Abstract. Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg̸ml x min on day 1) and docetaxel (60 mg/m 2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high-and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration. IntroductionCyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins (PGs), is expressed in a number of solid tumors and is associated with carcinogenesis, tumor proliferation, infiltration, metastasis, angiogenesis and resistance to anticancer drugs (1). In lung cancer cells, COX-2, which is particularly overexpressed in adenocarcinoma (2), is considered to be a negative predictor of survival in this subpopulation (3-7). Based on these reports, several clinical trials have been conducted for the potentiation of targeting COX-2 in lung cancer (8).The cyclin-dependent kinase (Cdk) inhibitor p27 plays a critical role in cell cycle regulation from the G1 to the S phase by inhibiting Cdk4/6-cyclin D1 and Cdk2-cyclin E (9). Loss of p27 expression tends to be an unfavorable prognostic factor in patients with non-small-cell lung cancer (NSCLC) (10). Increased p27 expression is attributed to COX-2-independent mechanisms of G0/G1 arrest driven by COX-2 inhibitors (11). Thus, p27 expression may be another predictive factor of the response to COX-2 inhibitors.Taxanes, such as paclitaxel and docetaxel, are microtubule-stabilizing agents that act by interfering with spindle microtubule dynamics, causing cell cycle arrest and apoptosis through activating a number of molecular pathways (12,13). Taxanes are able to drive COX-2...

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Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling

Cited by 63 publications

References 37 publications

IL-1β-Mediated Up-Regulation of WT1D via miR-144-3p and Their Synergistic Effect with NF-κB/COX-2/HIF-1α Pathway on Cell Proliferation in LUAD

IL-1β-Mediated Up-Regulation of WT1D via miR-144-3p and Their Synergistic Effect with NF-κB/COX-2/HIF-1α Pathway on Cell Proliferation in LUAD

DDR2 facilitates papillary thyroid carcinoma epithelial mesenchymal transition by activating ERK2/Snail1 pathway

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

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