NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation.
Naringin, which is one of the flavonoids contained in citrus fruits, is well known to possess various healthy functions to humans. It has been reported that naringin suppresses cancer cell growth in vitro and in vivo, although the underlying mechanisms are not fully understood. Recently, the roles of glycoconjugates, such as gangliosides, in cancer cells have been focused because of their regulatory effects of malignant phenotypes. Here, to clarify the roles of naringin in the negative-regulation of cancer cell growth, the alteration of glycoconjugates induced by naringin exposure and its significance on cell signaling were investigated. Human cancer cells, HeLa and A549, were exposed to various concentrations of naringin. Naringin treatment induced the suppression of cell growth toward HeLa and A549 cells accompanied with an increase of apoptotic cells. In naringin-exposed cells, GM3 ganglioside was drastically increased compared to the GM3 content prior to the treatment. Furthermore, naringin inhibited NEU3 sialidase, a GM3 degrading glycosidase. Similarly, NEU3 inhibition activities were also detected by other flavanone, such as hesperidin and neohesperidin dihydrocalcone, but their aglycones showed less inhibitions. Naringin-treated cancer cells showed suppressed EGFR and ERK phosphorylation levels. These results suggest a novel mechanism of naringin in the suppression of cancer cell growth through the alteration of glycolipids. NEU3 inhibitory effect of naringin induced GM3 accumulation in HeLa and A549 cells, leading the attenuation of EGFR/ERK signaling accompanied with a decrease in cell growth.
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan.
Ayana
A
Yoshinaga
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan.
Natsuki
N
Kajiya
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan.
Kazuki
K
Oishi
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan.
Yuko
Y
Kamada
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan.
Asami
A
Ikeda
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan.
Petros Kingstone
PK
Chigwechokha
Department of Biochemistry and Genetic, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Toshiro
T
Kibe
Department of Biochemistry and Genetic, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Michiko
M
Kishida
Department of Biochemistry and Genetic, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Shosei
S
Kishida
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan.
Masaharu
M
Komatsu
Faculty of Fisheries, Kagoshima University, Kagoshima, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan. Electronic address: shiozaki@fish.kagoshima-u.ac.jp.
Kazuhiro
K
Shiozaki
D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D005679:G(M3) Ganglioside / Q000378:metabolism*; D006001:Glycoconjugates / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D044950:Flavanones; D005679:G(M3) Ganglioside; D006001:Glycoconjugates; D065089:Glycoside Hydrolase Inhibitors; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C465436:Neu3 protein, human; D009439:Neuraminidase; C005274:naringin
EGFR; Flavanone; Ganglioside GM3; Naringin; Sialidase NEU3