Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction

Ku-Chung Chen ^a,b,1, Wen-Hsien Hsu ^c,1, Jhih-Yun Ho ^b, Cheng-Wei Lin ^a,b, Cheng-Ying Chu ^d, Chithan C. Kandaswami ^e, Ming-Ting Lee ^f, Chia-Hsiung Cheng ^a,b,*

^a Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

^b Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

^c Department of Surgery, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan

^d Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan

^e Castle Hills Health, Coimbatore, India

^f Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

Flavonoids luteolin and quercetin can inhibit growth and metastasis of cancer cells. In our previous report, luteolin and quercetin was shown to block Akt/mTOR/c-Myc signaling. Here, we found luteolin and quercetin reduced protein level and transactivation activity of RPS19 in A431-III cells, which is isolated from parental A431 (A431-P) cell line. Further investigation the inhibitory mechanism of luteolin and quercetin on RPS19, we found c- Myc binding sites on RPS19 promoter. The Akt inhibitor LY294002, mTOR inhibitor rapamycin and c-Myc inhibitor 10058-F4 significantly suppressed RPS19 expression and transactivation activities. Overexpression and knockdown of c-Myc in cancer cells show RPS19 expression was regulated by c-Myc. Furthermore, Knockdown and overexpression of RPS19 was used to analyze of the function of RPS19 in cancer cells. The epithelialmesenchymal transition (EMT) markers and metastasis abilities of cancer cells were also

regulated by RPS19. These data suggest that luteolin and quercetin might inhibit metastasis of cancer cells by blocking Akt/mTOR/c-Myc signaling pathway to suppress RPS19-activated EMT signaling.

Keywords: Luteolin, Quercetin, c-Myc, RPS19, EMT