Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model

Li, Heyan; Wang, Shuo; Takayama, K.; Harada, Taishi; Okamoto, Isamu; Iwama, Eiji; Fujii, Akiko; Ota, Keiichi; Hidaka, Noriaki; Kawano, Yuko; Nakanishi, Yoichi

doi:10.1016/j.lungcan.2015.01.017

Cited by 31 publications

(33 citation statements)

References 38 publications

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“…However, a few studies have demonstrated the effect of nicotine on anti-EGFR cancer therapy. In non-small cell lung cancer, nicotine induces resistance to erlotinib and gefitinib, which are EGFR tyrosine kinase inhibitors (23,46). In colorectal cancer, cigarette smoking during anticancer treatment with a cetuximab-based regimen reduces the therapeutic benefit (47).…”

Section: Discussionmentioning

confidence: 99%

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Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

et al. 2018

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Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

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Section: Discussionmentioning

confidence: 99%

“…Specifically, nicotine decreases the expression of EGFR, and enhances the accumulation of p-EGFR in the nucleus, thereby increasing proliferation of breast cancer cells (22). Finally, in lung cancer cells, nicotine serves a role in the resistance against EGFR inhibitors (23,24).…”

Section: Introductionmentioning

confidence: 99%

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

et al. 2018

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“…Therefore, nAChRs may be a promising molecular target to arrest lung cancer progression and reopen mitochondrial apoptotic pathways. Nicotine can induce erlotinib resistance via the crosstalk between α1nAChR and EGFR/AKT/ ERK signaling pathways in NSCLC [117]. A recent study suggested that smoking containing nicotine causes resistance to erlotinib therapy in NSCLC [118].…”

Section: The Potential Mechanisms Of Nicotine and Sirtuins On Drug Rementioning

confidence: 99%

“…nAChR signaling in mitochondria is stimulated and engages PI3K/AKT kinases, similar to those activated by plasma membrane nAChRs. Nicotine contributes to progression and erlotinib resistance in an NSCLC xenograft model through the nAChR-EGFR cooperation [117]. The nicotine-mediated α5nAChR/ AKT signaling pathway prevents cisplatin-induced cancer cell apoptosis [112].…”

Section: Sirt2-sirt7mentioning

confidence: 99%

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

Cheng

Chen

Lee³

et al. 2020

J. Cancer

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Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated with lung cancer risk and drug resistance. We focused on nAChR pathways activated by nicotine and its downstream signaling involved in regulating apoptotic factors of mitochondria and drug resistance in lung cancer. Increasing evidence suggests that several sirtuins play a critical role in multiple aspects of cancer drug resistance. Thus, understanding the consequences of crosstalk between nicotine/nAChRs and sirtuin signaling pathways in the regulation of drug resistance could be a critical implication for cancer therapy.

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“…Surprisingly, to our knowledge, only one study has been published involving systemic coadministration of nicotine and cancer chemotherapy in vivo. Li et al (2015) observed significant increases in PC9 human lung adenocarcinoma tumor volume in BALB/c nude mice following administration of erlotinib (100 mg/kg, by mouth) for 10 days in combination with 100 mg/ml nicotine in the drinking water or given i.v. (0.6 mg/kg, 5Â/week) when compared with erlotinib alone.…”

Section: Studies In Tumor-bearing Animalsmentioning

confidence: 99%

The Influence of Nicotine on Lung Tumor Growth, Cancer Chemotherapy, and Chemotherapy-Induced Peripheral Neuropathy

Kyte

Gewirtz

2018

J Pharmacol Exp Ther

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Studies in animal models have suggested that nicotine, an agonist of nicotinic acetylcholine receptors, may have the potential to prevent and/or reverse the peripheral neuropathy induced by cancer chemotherapeutic drugs, such as paclitaxel and oxaliplatin. However, a large body of evidence suggests that nicotine may also stimulate lung tumor growth and/or interfere with the effectiveness of cancer chemotherapy. Whereas the reported proliferative effects of nicotine are highly variable, the antagonism of antitumor drug efficacy is more consistent, although this latter effect has been demonstrated primarily in cell culture studies. In contrast, in vitro and in vivo studies from our own laboratory indicate that nicotine fails to enhance the growth of nonsmall cell lung cancer cells or attenuate the effects of chemotherapy (paclitaxel). Given the inconsistencies in the literature, coupled with our own findings, the weight of evidence suggests that caution may be warranted in proposing to use nicotine to mitigate chemotherapy-induced peripheral neuropathy in cancer patients receiving chemotherapy. Conversely, clinical trials could be performed in patients who have completed therapy and are considered to be disease-free to determine whether nicotine, in the form of commercially available patches or gum, is effective in alleviating peripheral neuropathy symptoms.

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Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model

Abstract: These results suggest that nicotine contributes to the progression and erlotinib-resistance of the NSCLC xenograft model via the cooperation between nAChR and EGFR.

Cited by 31 publications

References 38 publications

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

The Influence of Nicotine on Lung Tumor Growth, Cancer Chemotherapy, and Chemotherapy-Induced Peripheral Neuropathy

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