Abstract
Nobiletin (NOB) is a polymethoxylated flavonoid isolated from citrus fruit peel that has been shown to possess anti-tumor, antithrombotic, antifungal, anti-inflammatory and anti-atherosclerotic activities. The main purpose of this study was to explore the potential of using NOB to induce apoptosis in human bladder cancer cells and study the underlying mechanism. Using an MTT assay, agarose gel electrophoresis, a wound-healing assay, flow cytometry, and western blot analysis, this study investigated the signaling pathways involved in NOB-induced apoptosis in BFTC human bladder cancer cells. Our results showed that NOB at concentrations of 60, 80, and 100 μM inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 μM NOB demonstrated increased DNA fragmentation, and flow cytometry analysis confirmed that the treatment caused late apoptotic cell death. Western blot analysis showed that mitochondrial dysfunction occurred in NOB-treated BFTC cells, leading to cytochrome C release into cytosol, activation of pro-apoptotic proteins (caspase-3, caspase-9, Bad, and Bax), and inhibition of anti-apoptotic proteins (Mcl-1, Bcl-xl, and Bcl-2). NOB-induced apoptosis was also mediated by regulating endoplasmic reticulum stress via the PERK/elF2α/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic effects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction.
Highlights
Urothelial carcinoma of the transitional epithelium is called transitional cell carcinoma (TCC), and can develop in the urothelium of the renal pelvis, ureter, or bladder
The results showed that at concentrations ranging from 60 to 100 μM, BFTC cell growth was significantly inhibited, and the inhibitory effect was positively correlated with the NOB concentration (Figure 1A)
The results demonstrated that NOB at concentrations of 60, 80, and 100 μM inhibited BFTC cell growth the results demonstrated that NOB at concentrations of 60, 80, and 100 μM inhibited BFTC cell growth (Figure 1A), and the inhibition effect of NOB on the bladder cancer cell line was positively correlated (Figure 1A), and the inhibition effect of NOB on the bladder cancer cell line was positively correlated with the concentration of NOB
Summary
Urothelial carcinoma of the transitional epithelium is called transitional cell carcinoma (TCC), and can develop in the urothelium of the renal pelvis, ureter, or bladder. Urothelial carcinoma is the fifth most malignant tumor in the world, and the second most common cancer of the genitourinary tract [1,2]. Clinical evidence has demonstrated that urothelial carcinoma accounts for approximately 90–95% of Molecules 2019, 24, 2881; doi:10.3390/molecules24162881 www.mdpi.com/journal/molecules. Molecules 2019, 24, 2881 all bladder cancers, and more than 90% of human bladder tumors are TCCs [3,4]. TCC is an important disease in the aging population, especially as the proportion of women suffering from cancer increases with age [5]. The most common treatment for bladder TCC is surgical removal, followed by immunotherapy and chemotherapy.
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