Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C

Abstract

Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

Protein Kinase C (PKC) Isozymes and Cancer

“…Cigarette smoke exposure, including secondhand (passive or environmental) smoke exposure, causes damage and/or apoptosis of lung cells and increases the risk of lung cancer [328]. PKC signaling has been shown to be involved in smoke-induced cell damage and apoptosis [328][329][330], but there is very little data specifically on the role of PKC isozymes in causing cigarette smoke-induced lung cancer. In a recent study, smoke exposure induces the phosphorylation of tumor necrosis factor-convertase (TACE; also known as ADAM17), which is a metalloprotease disintegrin.…”

Whole-Genome Sequencing of Asian Lung Cancers: Second-Hand Smoke Unlikely to Be Responsible for Higher Incidence of Lung Cancer among Asian Never-Smokers

“…The axonal pathfinding/WNT signaling pathway is implicated in various cancers (36,37). The multi-hit variant list revealed mutations in NTRK3 and SLITRK1 as well as a putative translocation involving NTRK2 (observed in structural variant analysis; Supplementary Table S4).…”

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

“…Mechanistically, Wnt5a could regulate ATP-binding cassette, subfamily B (ABCB1, P-gp, and MDR1) expression in multidrug-resistant cancer cells through activation of the noncanonical protein kinase A (PKA)/ β -catenin pathway [22]. In the lung, Wnt5a was found to correlate with cigarette smoke-related lung carcinogenesis by a mechanism of activating PKC/Akt pathway [23], by which Wnt5a inhibited lung cancer cell apoptosis [14]. Therefore, the noncanonical Wnt signaling, such as Wnt5a, has been suggested as potential therapeutic targets in cancers [24, 25].…”