Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Zhao, Qingnan; Gu, Xiajing; Zhang, Chun; Lü, Qing; Chen, Hongzhuan; Xu, Lu

doi:10.1080/15384047.2015.1029835

Cited by 34 publications

(34 citation statements)

References 37 publications

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“…In addition to a number of examples discussed above, emerging evidence would suggest that such inhibitors could be useful in combination with Bcl-2 75, 76 and HSP90 inhibitors 77 . In these contexts, inhibition of ERK1/2 activity may prevent the activation of pro-survival pathways or could further limit anti-proliferative effects.…”

Section: Discussionmentioning

confidence: 99%

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cristea

Sage

2016

Journal of Thoracic Oncology

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The activity of the RAF-MEK-ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF-MEK-ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF-MEK-ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. Based on these observations, we examine when small molecules targeting kinases in the RAF-MEK-ERK pathway may be useful therapeutically in SCLC patients, including in combination with other therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Cristea

Sage

2016

Journal of Thoracic Oncology

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“…Additionally, there are data regarding the possibly implication of EMT in response to treatment with ALK inhibitors among patients with EML4-ALK NSCLC (45). Finally, there are some data referring to possible ways for reversion of the EMT in NSCLC, such as blocking muscarinic receptor signaling in vitro and in vivo, indicating that probably non-neuronal acetylcholine promotes EMT partially through activation of muscarinic receptor M2R (46).…”

Section: Discussionmentioning

confidence: 99%

Epithelial–Mesenchymal Transition in Non Small-cell Lung Cancer

2017

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Abstract. Background/Aim: Lung cancer is the first cause of cancer related deaths in both males and females. Epithelialmesenchymal transition (EMT) is a reversible process by which epithelial cells transform to mesenchymal stem cells by losing their cell polarity and cell-to-cell adhesionLung cancer is the first cause of cancer-related deaths in both males and females. It is a fatal disease and most patients with lung cancer will die of their disease (1). Two main types of lung cancer exist: non-small-cell lung cancer (NSCLC) accounting for 85-90% of lung cancer cases, and small-cell lung cancer (SCLC), whose incidence seems to have decreased over the past decades (2). The current therapeutic approach for lung cancer includes surgical tumor removal, platinum-based chemotherapy, targeted therapy, immunotherapy and radiation therapy. Improvements in clinical and molecular understanding of the disease have resulted in novel therapeutic approaches. Multiple genetic and epigenetic abnormalities results in both oncogene activation [epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)] and inactivation of tumor-suppressor genes [transcription factor (p53) and retinoblastoma protein (RB)] (3). Moreover, angiogenesis seems to play an important role in the process of invasion and metastasis in lung cancer (4). Other molecular and cellular processes of lung cancer include genomic instability, escape from apoptosis, cell immortalization, abnormalities in immune response and epithelial-mesenchymal transition (EMT) (5-9).

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“…Moreover, auto-paracrine non-neuronal acetylcholine, acting as a growth factor, stimulates tumor proliferation in NSCLC by activating CHRM2. In contrast, blocking CHRM2 arrests tumor cell growth in NSCLC [96, 97]. …”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Cen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. Methods: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. Results: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. Conclusion: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

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Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

Cited by 34 publications

References 37 publications

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

Epithelial–Mesenchymal Transition in Non Small-cell Lung Cancer

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

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