Fisetin Suppresses the Proliferation and Metastasis of Renal Cell Carcinoma through Upregulation of MEK/ERK-Targeting CTSS and ADAM9.

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.

• Authors: Min-Hong Hsieh, Jen-Pi Tsai, Shun-Fa Yang, Hui-Ling Chiou, Chia-Liang Lin, Yi-Hsien Hsieh, Horng-Rong Chang
• Journal: Cells (Cells) Vol. 8 Issue 9 (08 21 2019) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 31438640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Flavonoids
• Flavonols
• Membrane Proteins
• Cathepsins
• cathepsin S
• ADAM Proteins
• ADAM9 protein, human
• fisetin

Topics

• ADAM Proteins (metabolism)
• Antineoplastic Agents (chemistry, pharmacology)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cathepsins (metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Flavonoids (chemistry, pharmacology)
• Flavonols
• Humans
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Membrane Proteins (metabolism)
• Molecular Structure
• Neoplasm Metastasis (drug therapy)
• Structure-Activity Relationship
• Tumor Cells, Cultured