Molecular Mechanisms of Cigarette Smoke-Induced Proliferation of Lung Cells and Prevention by Vitamin C

Abstract

Lung cancer is the leading cause of cancer dearth. Cigarette smoking is the strongest risk factor for developing lung cancer, which is conceivably initiated by proliferation. Here, we show that low concentration of aqueous extract of cigarette smoke (AECS) causes excessive proliferation of human lung epithelial cells (A549) without any apoptotic cell death. The causative factor responsible for AECS-induced proliferation has been identified as p-benzoquinone (p-BQ). Coimmunoprecipitation and immunoblot experiments indicate that p-BQ binds with epidermal growth factor receptor (EGFR). However, in contrast to EGF, it causes aberrant phosphorylation of EGFR that lacks c-Cbl-mediated ubiquitination and degradation resulting in persistent activation of EGFR. This is followed by activation of Hras + Kras and the downstream survival and proliferative signaling molecules Akt and ERK1/2, as well as the nuclear transcription factors c-Myc and c-Fos. Vitamin C and/or antibody to p-BQ prevents AECS/p-BQ-induced proliferation of lung cells apparently by inactivating p-BQ and thereby preventing activation of EGFR and the downstream signaling molecules. The results suggest that vitamin C and/or antibody to p-BQ may provide a novel intervention for preventing initiation of lung cancer in smokers.

p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C

“…Previous reports from our laboratory had indicated that p-BQ derived from cigarette smoke binds to the extracellular domain of EGFR in cultured human lung cells and activates EGFR constitutively [16] . Here, we showed binding of p-BQ with EGFR in the renal pelvis of vitamin C-restricted guinea pigs those developed CIS.…”

“…Previously we had shown that p-BQ derived from CS activated EGFR and acted like a mitogen in cultured human lung cells [16] . Here, we showed that p-BQ activated EGFR in the renal pelvis apparently by binding to cysteine or lysine residues of the extracellular domain and induced aberrant phosphorylation of cytoplasmic tyrosine residuesinsert reference [17] .…”

“…It is produced from p-benzosemiquinone (p-BSQ), a long-lived semiquinone of cigarette smoke (CS) in vivo, by disproportionation and oxidation [11] . p-BSQ is present in substantial amounts (100–200 μg) in commercial cigarettes [16] . We have observed that in the lung, p-BQ closely mimics emphysema in a guinea pig model [14] .…”

“…Previously we had shown that p-BQ acts like a mitogen in vitro. It induces proliferation of cultured human lung cells through activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathway [16] . EGFR signaling is known to play a key role in UC [19] , [20] .…”

Cancer Preventive and Therapeutic Properties of Fruits and Vegetables Against Lung Cancer

“…A number studies have shown that vitamin C inhibits proliferation of lung cancer cells, and demonstrates synergism with tea polyphenols by modulating different signaling pathways. [32][33][34][35] Studies have also shown that combination of ascorbic acid and α-tocopherol prevented smoke-induced lung squamous metaplasia in ferrets, 36 and a combination of vitamin C and vitamin K3 inhibited tumor growth and metastasis of Lewis lung carcinoma xenograft in mice. 37 In the 1970s, Linus Pauling promoted the use of vitamin C to prevent the common cold, and later for the treatment of cancer including lung cancer.…”