Mounting evidences have revealed that benzidine, a known human carcinogen, is a pivotal risk factor for bladder cancer (BC). Dysregulated cell proliferation serves as a pivotal pathophysiological step in BC development. The potential mechanisms of MAPK pathways, particularly extracellular regulated protein kinases 5 (ERK5), regarding the modulation of benzidine-elicited cell proliferation are still elusive. Herein, human BC cells UMUC-3 were exposed to indicated levels of benzidine for 5 days. Cell growth, cell cycle progression, cell cycle-related, MAPK genetic expression, and related protein contents were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, flow cytometry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and western blotting (WB), respectively. XMD8-92 (a specific suppressor of ERK5) and small interfering RNA (siRNA) were utilized to identify the roles of ERK5. Our results illustrated that benzidine elevated the proliferative ability of UMUC3 cells and accelerated the cell cycle transition from G1 to S phase, and it increased the expressions of cyclin D1 and proliferating cell nuclear antigen (PCNA) and reduced the expression of p21. Meanwhile, benzidine treatment resulted in the activation of ERK5 pathway and activator protein 1 (AP-1) proteins. In addition, benzidine-elicited cell proliferation and ERK5 stimulation were fully inhibited by XMD8-92 and siRNAs specific to ERK5. Taken together, these results demonstrated that ERK5-mediated cell proliferation was tightly related to benzidine-assoicated BC development, which established the foundation for targeting the ERK5 pathway in BC treatment.
Cigarette smoke (CS) is a main risk factor for bladder cancer (BC). The epithelial-to-mesenchymal transition (EMT), termed as an embryonic program, participates in the development process of CS-associated BC. Over the last decade, the effects and mechanisms of curcumin on CS-related BC have been extensively investigated. However, it's still elusive if MAPK pathways participate in curcumin-associated protective effect against CS-related promotive role in BC. In this study, our results showed that the exposure of BC cells UMUC3 to cigarette smoke extract (CSE) induced morphology variation, reinforced migratory and invasive abilities, decreased epithelium biomarker expression and increased mesenchyme biomarker expression. Meanwhile, CSE administration led to the stimulation of extracellular regulated protein kinases 1 and 2 (ERK1/2) and activator protein 1 (AP-1) proteins, without validly activating the Jun N-terminal kinase (JNK), p38 or ERK5 pathway. Moreover, CSE-elicited EMT and ERK1/2/AP-1 stimulation were completely diminished by U0126, a pharmacological inhibitor targeting ERK1/2. Furthermore, the co-treatment with low concentrations of curcumin significantly abolished CSE-elicited EMT in UMUC3 cells, and the ERK1/2/AP-1 pathway was implicated in the suppressive effect. In summary, these data indicated the modulatory effects of ERK1/2 on CSE-elicited urocystic EMT in vitro and the chemoprevention efficacy of curcumin.
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