Abstract
Fisetin, a natural flavonoid, is known to have anticarcinogenic effects against several cancers, but its role in mediating renal cell carcinoma (RCC) progression has not been delineated. Cell viability, cytotoxicity, and cell cycle distribution were measured using the 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and propidium iodide staining with flow cytometry. The in vitro migration and invasion assay was used to examine in vivo cell migration and invasion. Human protease antibody array analysis was conducted with cell migration/invasion-related proteins. Western blotting and quantitative reverse transcription polymerase chain reaction were used for assessing protein expression related to the cell cycle, cell invasion, and mitogen-activated protein kinase (MAPK) signaling pathway. We found that fisetin significantly inhibited cell viability through cell cycle arrest in the G2/M phase, in addition to downregulating cyclin D1 and upregulating p21/p27. Fisetin inhibited the migration and invasion of human RCC cells through the downregulation of CTSS and a disintegrin and metalloproteinase 9 (ADAM9). Fisetin also upregulated ERK phosphorylation in 786-O and Caki-1 cells. Furthermore, treatment with a MEK inhibitor (UO126) reduced the inhibitory effects of fisetin on the metastasis of RCC cells through the ERK/CTSS/ADAM9 pathway. Fisetin inhibits proliferation and metastasis of RCC cells by downregulating CTSS and ADAM9 through the MEK/ERK signaling pathway. These findings indicate that fisetin is a promising antitumor agent against RCC.
Highlights
Renal cell carcinoma (RCC) is the most lethal genitourinary cancer in patients with advanced or metastatic renal cell carcinoma (RCC), leading to a poor prognosis [1]
Through the modulation of the caspase-dependent pathway and the interruption of the p38 mitogen-activated protein kinase (MAPK)-dependent pathway, we found that fisetin can induce apoptosis and inhibit the migration and invasion of human cervical cancer cells [12,13]
We found that fisetin combined with Rh-a disintegrin and metalloproteinase 9 (ADAM9) or Rh-cathepsin S (CTSS) significantly restored the migration and invasion of 786-O and Caki-1 cells compared with fisetin alone (Figure 7A,B)
Summary
Renal cell carcinoma (RCC) is the most lethal genitourinary cancer in patients with advanced or metastatic RCC, leading to a poor prognosis [1]. Cells 2019, 8, 948 be used for RCC treatment; if metastasis is present, immunotherapeutic agents in addition to nephrectomy are needed to increase the median survival time [2]. Fisetin (3,30 ,40 ,7-tetrahydroxyfavone), a naturally occurring flavonoid commonly found in plants, is effective against cancer, and its possible mechanisms include inhibition of proliferation, angiogenesis, induction of cell cycle arrest, and reversal of multidrug resistance [7]. Through the modulation of the caspase-dependent pathway and the interruption of the p38 mitogen-activated protein kinase (MAPK)-dependent pathway, we found that fisetin can induce apoptosis and inhibit the migration and invasion of human cervical cancer cells [12,13]
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