Nicotine induces cell survival and chemoresistance by stimulating Mcl‐1 phosphorylation and its interaction with Bak in lung cancer

Abstract

Nicotine is a major carcinogen in cigarettes, which can enhance cell proliferation and metastasis and increase the chemoresistance of cancer cells. Our previous data found that nicotine promotes cell survival in lung cancer by affecting the expression of antiapoptotic protein Mcl‐1, suggesting that the Mcl‐1 may be a therapeutic target for patients with lung cancer. In this study, we found that the effects of drug resistance on nicotine‐induced lung cancer cell lines were shown to influence the phosphorylation of Mcl‐1. Moreover, nicotine induces Mcl‐1 phosphorylation exclusively at the T163 site, which results in enhancement of the antiapoptotic activity of Mcl‐1 and increased cell survival. Meanwhile, nicotine can reduce the sensitivity of H1299 cells to CDDP via enhancement of the binding of Mcl‐1 to Bak, which inhibits the proapoptotic effect of Bak and ultimately leads to increased survival and drug resistance of lung cancer cells. Thus, nicotine‐induced cell survival and chemoresistance may occur in a mechanism by stimulating Mcl‐1 phosphorylation and its interaction with Bak, which may contribute to improving the efficacy of chemotherapy in the treatment of human lung cancer.

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

“…Overexpression of Mcl-1 is frequently observed in human cancers, including NSCLC 37 , colorectal 38 , liver 39 , prostate cancer 40 , and multiple myeloma 41 . High level of Mcl-1 often related to poor prognosis and conferred resistance to chemo/radiotherapy [42][43][44][45][46][47] . A recent study showed that TWEAK stimulation of NSCLC cells induced NF-κB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo-and radioresistance 48 .…”

Nicotine-Induced ILF2 Facilitates Nuclear mRNA Export of Pluripotency Factors to Promote Stemness and Chemoresistance in Human Esophageal Cancer

“…Retrospective studies showed that lifestyle factors, particularly smoking, are strongly associated with poor prognosis in patients with esophageal cancer, especially those treated by chemoradiotherapy, suggesting that smoking can induce chemoresistance (2,25). Indeed, nicotine treatment induces chemoresistance in diverse human solid tumors (39)(40)(41). Thus, it is necessary to identify novel key downstream effectors of smoking in esophageal cancer.…”

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

“…Dysfunctions in cell death signaling and the overactivation of cell survival molecules are commonly observed in lung cancer. , Lung cancer has demonstrated the ability to acquire resistance mechanisms through various pathways even with the advent of targeted therapies. , Intriguingly, serum from smokers can enhance resistance to erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and cisplatin-induced lung cancer cell death by activating AKT signaling. − An increased antiapoptotic protein Bcl-2 expression generally plays a crucial role in apoptotic resistance. , Nicotine has been reported to stabilize Bcl-2 by preventing its degradation through the ubiquitin-proteasomal pathway, thereby reducing sensitivity to cisplatin in lung cancer cells . Furthermore, nicotine-induced AKT activation causes antiapoptotic protein Mcl-1 phosphorylation, which promotes its antiapoptotic activity by inhibiting the pro-apoptotic protein Bak . This phenomenon contributes to the chemotherapy resistance.…”

“…49 Furthermore, nicotine-induced AKT activation causes antiapoptotic protein Mcl-1 phosphorylation, which promotes its antiapoptotic activity by inhibiting the pro-apoptotic protein Bak. 50 This phenomenon contributes to the chemotherapy resistance. The antagonist of α7 nAChR, APS8, which is a synthetic alkylpyridinium polymer, induces mitochondrial depolarization and promotes apoptosis in lung cancer cells in vitro.…”