Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway

Xu, Ran; Shang, Chao; Zhao, Jungang; Ye, Han; Li, Jun; Chen, Kuanbing; Shi, Wenjun

doi:10.1007/s13277-014-2911-z

Cited by 40 publications

(31 citation statements)

References 28 publications

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“…EGFR has been shown to play important roles in the modulation of chondrocyte activity and functions following chemical stimuli [17,18]. Moreover, the relationship among EGFR, PKC, and PI3K has been alluded to in some studies concerning signaling transduction of other cells [19,20]. Following periodic mechanical stress, the role of EGFR in mechanosensing, signaling transduction, and final mitogenic effects in chondrocytes, including the nature of any functional association among EGFR, PKC, and PI3K in this system, is yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Shen

Gao

et al. 2016

Cell Physiol Biochem

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Background/Aims: The present study aimed to analyze the mechanisms by which periodic mechanical stress is translated into biochemical signals, and to verify the important role of signaling molecules including phosphatidylinositol-3-kinase (PI3K)-Akt, protein kinase C (PKC), and epidermal growth factor receptor (EGFR) in chondrocyte proliferation. The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress need further investigation. Methods: Two steps were undertaken in the experiment. In the first step, the cells were pretreated with shRNA targeted to Akt or EGFR or PKCδ or control scrambled shRNA. Moreover, they were pretreated with LY294002, GF109203X, Gö6976, rottlerin, and AG1478. They were maintained under static conditions or periodic mechanical stress for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. In the second step, the cells were pretreated with shRNA targeted to Akt or EGFR or PKCδ or control scrambled shRNA. Moreover, they were pretreated with LY294002, AG1478, and rottlerin. They were maintained under static conditions or periodic mechanical stress for 1 h prior to Western blot analysis. Results: Proliferation was inhibited by pretreatment with PKC or PKCδ inhibitor GF109203X or rottlerin and by short hairpin RNA (shRNA) targeted to PKCδ, but not by PKCα inhibitor Gö6976 in chondrocytes in response to periodic mechanical stress. Meantime, rottlerin and shRNA targeted to PKCδ also attenuated EGFR, Akt, and ERK1/2 activation. Furthermore, inhibiting EGFR activity by AG1478 and shRNA targeted to EGFR abrogated chondrocyte proliferation and phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK)1/2 subjected to periodic mechanical stress, while the phosphorylation site of PKCδ was not affected. In addition, pretreatment with the PI3K-Akt-selective inhibitor LY294002 and shRNA targeted to Akt reduced periodic mechanical stress-induced chondrocyte proliferation and phosphorylation of ERK1/2, while the phosphorylation levels of EGFR and PKCδ were not inhibited. Conclusion: These findings suggested that periodic mechanical stress promoted chondrocyte proliferation through PKCδ-EGFR-PI3K-Akt-ERK1/2. They provide a stronger viewpoint for further investigations into chondrocyte mechanobiology under periodic mechanical stress and the ways to improve the quality of tissue-engineered cartilage.

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Section: Introductionmentioning

confidence: 99%

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Shen

Gao

et al. 2016

Cell Physiol Biochem

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“…On the other hand, M 3 R is highly expressed in gastric cancer tissue (Wang et al, 2016), lung cancer tissue (Lin, Sun, Wang, Guo, & Xie, 2014), and colon neoplasia (Cheng, Shang, Drachenberg, Zhan, & Raufman, 2017), and it is correlated with the cancer stage and lymph node metastasis. Some in vitro investigations showed that activation of M 3 R by acetylcholine promotes cell proliferation of nonsmall cell lung cancer cells (Xu et al, 2015) and human gastric cancer cells (Wang et al, 2016), whereas the knockdown of M 3 R by a small hairpin RNA (shRNA) inhibited cell proliferation of gastric cancer cells (Wang et al, 2016) and small cell lung cancer cells (Song et al, 2007). Our investigation showed that knocking down of M 3 R by specific siRNA did not affect cell proliferation of HNSCC cells, but the acacetininduced cell viability damage and cell apoptosis were inhibited by M 3 R knocking down, suggesting a potential M 3 R-related mechanism in acacetin-induced cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Acacetin‐induced cell apoptosis in head and neck squamous cell carcinoma cells: Evidence for the role of muscarinic M3 receptor

Sun

Peng

et al. 2019

Phytotherapy Research

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Aacacetin, a plant flavone has shown antitumor efficacy recently. However, its associated mechanisms are poorly known. We hypothesized that the muscarinic M3 receptor (M3R), which is highly expressed in some cancer tissue, is related to the antitumor effect of acacetin in head and neck squamous cell carcinoma (HNSCC) cells. Our results showed that 12.5‐ to 200‐μM acacetin inhibited cell viability in dose‐ and time‐dependent manners in HNSCC cells, but a relative higher concentration was needed for oral adenoid cystic carcinoma cells. M3R expression level was higher in HNSCC cells than that in adenoid cystic carcinoma cells. Flow cytometry and electron microscopy confirmed acacetin‐induced cell apoptosis in 22B cells, a HNSCC cell line. Acacetin promoted mitochondrial cytochrome c release and caspase 9, 3 processing. Knocking down of M3R expression by specific siRNA significantly prevented the acacetin‐induced cell viability damage, cell apoptosis, and caspase 3 activation. Besides, M3R was also involved in acacetin‐induced elevation of reactive oxygen species and intracellular calcium ([Ca2+]i). These data indicate that acacetin‐induced cell apoptosis in HNSCC cells may through M3R related calcium signaling and caspase 3 activation. Acacetin is a potent natural antitumor reagent especially for the tumor cells, which highly expressed M3R.

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“…Several aggressive tumors present an overexpression of the HER2 marker considering them a possible target in cancer therapy [31,32]. A variant with high homology of this marker is the EGFR which is also over-expressed in cancer [33,34], and whose activity is related to the increment in proliferation and invasion, and can be modulated by muscarinic receptors [35]. Our results demonstrated that the combination of PX plus carbachol or APE drastically reduced EGFR expression in tumor cells and this effect should be beneficial in the treatment of this type of tumor.…”

Section: Discussionmentioning

confidence: 99%

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype

Español

Salem

Bari

et al. 2019

Preprint

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35Triple negative tumors are more aggressive than other breast cancer subtypes 36 and there is a lack of specific therapeutic targets on them. Since muscarinic receptors 37 have been linked to tumor progression, we investigated the effect of metronomic 38 therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at 39 low doses on this type of tumor. We observed that MDA-MB231 tumor cells express 40 muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, 41 which was used as control. The addition of carbachol or arecaidine propargyl ester, a 42 non-selective or a selective subtype 2 muscarinic (M 2 ) receptor agonist respectively, 43 plus paclitaxel reduces cell viability involving a down-regulation in the expression of 44 ATP "binding cassette" G2 drug transporter and epidermal growth factor receptor. We 45 also detected an inhibition of tumor cell migration and anti-angiogenic effects produced 46 by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our 47 findings provide substantial evidence about M 2 receptors as therapeutic target for the 48 treatment of triple negative tumors. 49 50 51 Breast cancer is yet the most frequent type of malignancy in women and 52 represents a major and unsolved problem for public health [1]. Luminal and triple 53 negative (TN) represent the two opposite ends of the molecular classification of breast 54 tumors and they thoroughly differ regarding treatment and patients´survival [2]. The TN 55 tumors are typically larger in size, higher grade than other breast cancers, and they also 56 exhibit an aggressive clinical behavior, frequently resulting in early metastatic 57 dissemination, particularly to visceral sites. As a result of these characteristics, TN 58 breast cancers are associated with poor prognosis in comparison to luminal breast 59 tumors [3]. Considering the treatment of TN tumors, classical modalities have improved 60 the overall outlook and quality of life for women with this type of breast cancer.61However, because of recurrence and/or the development of resistance to cytotoxic drugs 62 administered to patients, produced by a complex mechanism mediated by different types 63 of proteins such as ATP "binding cassette" (ABC) transporters, a considerable amount 64 of patients still succumb to this disease highlighting the need to find new therapeutic 65 approaches [4]. Regarding the latter, the usage of low dose chemotherapy with short 66 drug free intervals, named metronomic therapy has emerged as a novel regimen for 67 cancer treatment [5]. It exerts very low incidence of side effects and could add new 3 68 beneficial actions on immune system and tumor microenvironment [6]. This new 69 strategy also needs the identification of new therapeutic targets to improve the benefits 70 for breast cancer patients. 71 Non-neuronal cholinergic system (nNCS) has been involved either in 72 physiological or in pathological processes. The nNCS is formed by acethylcholyne 73 (ACh), the enzymes...

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Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway

Cited by 40 publications

References 28 publications

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Acacetin‐induced cell apoptosis in head and neck squamous cell carcinoma cells: Evidence for the role of muscarinic M3 receptor

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype

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Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway

Cited by 40 publications

References 28 publications

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

Acacetin‐induced cell apoptosis in head and neck squamous cell carcinoma cells: Evidence for the role of muscarinic M3 receptor

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2receptor subtype

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The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype