Nicotine Promotes Mammary Tumor Migration via a Signaling Cascade Involving Protein Kinase C and cdc42

Guo, Jinjin; Ibaragi, Soichiro; Zhu, Tingyao; Luo, Ling-Yu; Hu, Guo‐fu; Hüppi, Petra Susan; Chen, Chang Yan

doi:10.1158/0008-5472.can-08-0131

Cited by 57 publications

(63 citation statements)

References 43 publications

(79 reference statements)

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“…The findings that nicotine did not induce migration in quiescent A549 cancer cells in the absence of HGF is inconsistent with the results of previous studies, which observed that nicotine itself exerts a pro-migratory effect in various types of cancer cells (10,(12)(13)(14)16,17). The reasoning behind the inconsistent results between the present study and previous studies remains uncertain, however, it may be attributed to differences in the experimental protocol.…”

Section: Discussioncontrasting

confidence: 99%

“…Recent evidence suggests that the tumor-promoting effects of nicotine result in increased proliferation, invasion, mesenchymal transition (EMT) and angiogenesis, and decreased cell death and apoptosis (4,(9)(10)(11)(12)(13)(14)(15)(16)(17). However, the molecular mechanisms by which nicotine promotes tumor progression are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

et al. 2015

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Abstract. Cigarette smoking not only promotes lung carcinogenesis, but it has also been demonstrated to promote the progression of lung cancer. Despite nicotine being a major component of cigarette smoke, it is not carcinogenic when acting alone. Instead, it is believed to function as a tumor promoter. Due to the fatal consequences of lung cancer being primarily associated with the processes of invasion and metastasis, the present study aimed to determine the effect of nicotine on the migratory activity of lung cancer cells. The effect of nicotine on the migration of lung cancer A549 cells was evaluated by a wound healing assay. Hepatocyte growth factor (HGF) was used as a pro-migratory stimulus. During several of the experiments, specific inhibitors of α7-nicotine acetylcholine receptor (α7-nAchR), phosphoinositide kinase-3 (PI3K) and extracellular signal-related kinase (ERK)1/2 were included. The phosphorylation levels of Akt and ERK1/2 were examined using a cell-based protein phosphorylation assay. It was observed that nicotine did not induce cell migration by itself, but that it instead promoted HGF-induced cell migration. The effects of nicotine were inhibited by the pretreatment of the cells with the α7-nAchR inhibitor, methyllycaconitine, and the PI3K inhibitor, LY294002. The mitogen-activated protein kinase/ERK kinase kinase inhibitor exerted modest, but non-significant inhibitory activity on the effect of nicotine. Nicotine did not induce Akt phosphorylation by itself, but instead promoted the HGF-induced phosphorylation of Akt. It was also observed that nicotine had no effect on ERK1/2 phosphorylation. The results from the present study indicate that nicotine, when alone, does not have a pro-migratory function, but instead enhances responsiveness to the pro-migratory stimulus emitted by HGF. The current study provides an insight into the mechanism of tumor promotion by demonstrating that nicotine and α7-nAchRs act in synergy with the HGF-induced PI3K/Akt signaling pathway, increasing the sensitivity of lung cancer cells to HGF, and thereby promoting cell migration, a vital step in invasion and metastasis. IntroductionLung cancer has one of the lowest survival rates of all types of cancer, accounting for 1.59 million mortalities in the world in 2012 (1). Smoking, particularly of cigarettes, is estimated to cause 87% of the lung cancer mortalities in men, and 70% of the lung cancer mortalities in women (2). Cigarette smoke contains numerous carcinogens, of which, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, are likely to serve major roles (3). However, recent evidence suggests that cigarette smoking not only promotes lung carcinogenesis, but that it also promotes the progression of lung cancer (4). For example, continued smoking during lung cancer treatment has been associated with decreased survival (5), while smoking cessation during the treatment improves the therapeutic outcome (6). Furthermore, cigarette smoking increases the r...

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

et al. 2015

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“…LPA and PA have both been reported to activate PKC signaling, which we have shown to be altered after EDI3 silencing. PKCα has previously been associated with the proliferation, migration, and invasion of tumor cells (36)(37)(38). The observation that EDI3 silencing decreases migration through the PKCα signaling pathway may have important implications for understanding the role of EDI3 in metastasis.…”

Section: Discussionmentioning

confidence: 95%

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Stewart

Marchan

Lesjak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.

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“…In other cancer cells, nicotine has been shown to affect various signaling cascades that initiated by the binding of its receptor. In breast cancer cells, nicotine was shown to promote cell migration through a signaling cascade involving protein kinase C (PKC) activation and its downstream effector cdc42 (20). In PDA cells, nicotine was shown to induce the expression of prometastasis and pro-angiogenesis osteopontin (OPN) through nAChR and downstream ERK1/2-dependent pathway (21,22).…”

Section: Discussionmentioning

confidence: 99%

Nicotine enhances invasion and metastasis of human colorectal cancer cells through the nicotinic acetylcholine receptor downstream p38 MAPK signaling pathway

et al. 2015

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Abstract. Nicotine as a cigarette component is an established risk factor for colorectal cancer tumorigenesis. The downstream signaling pathways of nicotinic acetylcholine receptors (nAchRs) are believed to be responsible for the cellular effects. In the present study, we evaluated the effects and novel mechanisms for nicotine on the capacity for colorectal cancer cell invasion and metastasis. LOVO and SW620 colorectal cancer cells were stimulated with nicotine in vitro. A Transwell chamber model was applied to detect the capacity for tumor cell invasion. Assays for gelatin zymography and western blotting were applied to detect the activity and expression of metastasis-related matrix metalloproteinases (MMPs), respectively. Signal transduction was assessed by immunoblotting for the phosphorylation of relevant signal molecules and the application of pharmaceutical inhibitors. We showed that nicotine increased LOVO and SW620 colorectal cancer cell invasion along with enhanced activity and expression of MMP-1, -2 and -9. Nicotine increased phosphorylation of p38, ERK, Akt and PI3K p85 but had no effect on phosphorylation of JNK, or NF-κB. Of the pharmaceutical inhibitors of U0126 (ERK1/2 inhibitor), LY294002 (Akt activation inhibitor), SB239063 (p38 MAPK activation inhibitor) and hexamethonium (Hex) (nAchRs inhibitor), the cellular and molecular effects were reduced by the applications of SB239063 and Hex. We concluded that nicotine stimulates the invasion and metastasis of colon cancer cells in vitro via activation of the nAchRs and the p38 MAPK downstream signaling pathway. Therefore, p38 MAPK may have potential as a therapeutic target for smoking-related human colorectal cancer metastasis.

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Nicotine Promotes Mammary Tumor Migration via a Signaling Cascade Involving Protein Kinase C and cdc42

Cited by 57 publications

References 43 publications

Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

Nicotine enhances hepatocyte growth factor-mediated lung cancer cell migration by activating the α7 nicotine acetylcholine receptor and phosphoinositide kinase-3-dependent pathway

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Nicotine enhances invasion and metastasis of human colorectal cancer cells through the nicotinic acetylcholine receptor downstream p38 MAPK signaling pathway

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