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Glutathione S-transferase A1 mediates nicotine-induced lung cancer cell metastasis by promoting epithelial-mesenchymal transition.

ABSTRACT: The present study aimed to investigate the effect of glutathione S-transferase A1 (GSTA1) on lung cancer cell viability, invasion and adhesion in the presence of nicotine in vitro. Furthermore, the effect of GSTA1 on the epithelial-mesenchymal transition (EMT), a process strongly associated with lung cancer metastasis, was examined. Human lung carcinoma A549 cells were treated with various concentrations of nicotine (0.01, 0.1, 1 and 10 µM) and levels of GSTA1 mRNA and protein were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. To knock down GSTA1 expression, GSTA1-small interfering RNA was transfected into A549 cells. Cell viability, invasion and adhesion abilities were determined by MTT, Transwell-Matrigel invasion and cell adhesion assays, respectively. The expression of the epithelial cell markers E-cadherin and keratin, and the mesenchymal cell markers vimentin and N-cadherin in A549 cells were examined by western blot analysis. The current study indicated that the expression of GSTA1 was increased in A549 cells following nicotine treatment. GSTA1 suppression inhibited the viability, invasion and adhesion of lung cancer cells. In addition, the increase in lung cancer cell viability, invasion and adhesion by nicotine was suppressed following GSTA1 knockdown. Furthermore, GSTA1 affected the expression of EMT markers in nicotine-treated or untreated lung cancer cells. Thus the present study demonstrates that GSTA1 promotes lung cancer cell invasion and adhesion and mediates the effect of nicotine on lung cancer cell metastasis in vitro. Furthermore, the results demonstrated that GSTA1 exerts its effect on lung cancer cell metastasis by promoting the EMT.

SUBMITTER: Wang W

PROVIDER: S-EPMC5526173 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:Background and Objective Annexin A1 (annexin I, ANXA1), the first discovered member of the annexin superfamily, plays important roles in tumor development, invasion, metastasis, apoptosis and drug resistance based on tumor type-specific patterns of expression. The acquisition of the epithelial-mesenchymal transition (EMT) characteristics is an essential mechanism of metastasis because they increase the mobility and invasiveness of cancer cells. Cancer invasion and metastasis remain major health problems worldwide. Elucidating the role and mechanism of ANXA1 in the occurrence of EMT will help advance the development of novel therapeutic strategies. Hence, this review aims to attract everyone’s attention to the important role of ANXA1 in tumors and provide new ideas for clinical tumor treatment. Methods The PubMed database was mainly used to search for various English research papers and reviews related to the role of ANXA1 in tumors and EMT published from November 1994 to April 2022. The search terms used mainly include ANXA1, EMT, tumor, cancer, carcinoma, and mechanism. Key Content and Findings This article mainly provides a summary of the roles of ANXA1 and EMT in tumor metastasis as well as the various mechanisms via which ANXA1 facilitates the occurrence of EMT, thereby affecting tumor metastasis. In addition, the expression of ANXA1 in different metastatic tumor cell lines and its roles in tumorigenesis and development are also elaborated. This article has found many tumorous therapeutic targets related to ANXA1 and EMT, further confirming that ANXA1 has a huge potential for the diagnosis, treatment and prognosis of certain cancers. Conclusions Both the abnormal expression of ANXA1 and the occurrence of EMT are closely related to the invasion and metastasis of tumors, and more interestingly, ANXA1 can impact EMT directly or indirectly by mediating signaling pathways and adhesion among cells. We need more studies to elucidate the effects of ANXA1 on tumor invasion, migration and metastasis through EMT in vitro and in vivo clearly, and ultimately in patients to identify more therapeutic targets.

Project description:Simple Summary Chemotherapeutic agents including cisplatin promote tumor metastasis while inhibiting tumor growth, which still represents a major obstacle for some patients in clinical practices. This study demonstrated that cisplatin induced epithelial-mesenchymal transition and tumor metastasis in lung adenocarcinoma. Further bioinformatic analysis showed that DCBLD2 may play a key role in metastasis after platinum chemotherapy. In terms of mechanism, DCBLD2 stabilized β-catenin through phosphorylation and inactivation of GSK3β, leading to the disintegration of the destruction complex of β-catenin. The accumulated β-catenin transported to the nucleus and promoted the expression of metastasis-related genes. In addition, cisplatin markedly enhanced DCBLD2 (Discoidin, CUB and LCCL domain containing 2) expression via ERK/AP-1 axis. Importantly, DCBLD2-specific siRNAs encapsulated by nanoparticles strikingly inhibited cisplatin-induced metastasis in tumor-bearing mice. Taken together, DCBLD2 mediates cisplatin-induced metastasis and DCBLD2 inhibition is a promising treatment option for preventing chemotherapy-induced metastasis. Abstract Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

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Glutathione S-transferase A1 mediates nicotine-induced lung cancer cell metastasis by promoting epithelial-mesenchymal transition.

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