Nicotinic-nAChR signaling mediates drug resistance in lung cancer

Our plain-English summary of Nicotinic-nAChR signaling mediates drug resistance in lung cancer, by W.L. Cheng, K.Y. Chen, K.Y. Lee, et al (Journal of Cancer, 2020).

The study

• Authors: W.L. Cheng, K.Y. Chen, K.Y. Lee, P.H. Feng, S.M. Wu
• Journal: Journal of Cancer
• Published: 2020;11(5):1125-1140
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© The author(s).

In plain English

This article is a review, not a new study. The authors summarized published laboratory, animal and patient research on how nicotine and tobacco-derived chemicals such as NNK and NNN act on nicotinic acetylcholine receptors (nAChRs) in lung cancer, and how this may relate to resistance to cancer drugs. Asbestos appears only once, in a list of lung cancer risk factors, and the article does not examine it. The authors described earlier studies linking one receptor type, α7nAChR, to lung cancer cell growth, spread and blood-vessel formation. They also reviewed proteins called sirtuins, tabulating studies on sirtuins and drug resistance across many cancers. From those studies they broadly grouped SIRT1, SIRT3 and SIRT5 to SIRT7 as tumor-promoting and SIRT2 and SIRT4 as tumor-suppressive. They also noted that these roles may depend on the tissue and that SIRT6 can act either way. The authors concluded that studies have suggested the nicotine/nAChR axis and SIRT1, SIRT3 and SIRT5 to SIRT7 mediate cancer drug resistance. They also concluded that blocking nicotine/nAChR and specific sirtuin signaling may enhance chemotherapy. They stated that the mechanisms still require elucidation and that SIRT1 may play contradictory roles.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research (no new data collected)
• Who was studied: No study population. The review drew on previously published cell, animal and patient studies of lung cancer and, for sirtuins, other cancer types.
• Exposure: Nicotine and its tobacco-derived derivatives NNK and NNN acting on nicotinic acetylcholine receptors. Asbestos is mentioned only as one of several lung cancer risk factors.
• Main results:
  • From the studies they reviewed, the authors summarized that nicotine acting through α7nAChR mediates lung cancer cell proliferation.
  • The authors summarized the reviewed studies as showing tumor progression modulated by SIRT1, SIRT3 and SIRT5 to SIRT7, and tumor-suppressive effects of SIRT2 and SIRT4.
  • The authors noted that whether a sirtuin acts as a tumor promoter or suppressor may depend on tissue. They said SIRT6 can play both roles in different cancers.
  • The review compiled published studies on the effects of sirtuins on drug resistance across many cancer types in a table.
  • The authors noted one clinical trial (NCT02416739) studying a sirtuin inhibitor (nicotinamide) combined with EGFR-TKI in non-small-cell lung cancer.
• The authors' conclusion: The authors concluded that studies have suggested the nicotine/nAChR axis and SIRT1/3/5-7 mediate cancer drug resistance. They also concluded that blocking signaling by nicotine/nAChR and specific sirtuins may enhance the efficacy of chemotherapy.
• Limitations the authors state:
  • The authors stated that the mechanisms by which nicotine signaling or specific sirtuin pathways lead to drug resistance still need to be worked out.
  • The authors noted that SIRT1 may promote or suppress tumors depending on the cell context or tumor type.
  • The authors stated that whether nicotine-mediated drug resistance in lung cancer involves long noncoding RNAs remains unclear.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Carcinoma.

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