Downregulation of HER2 by RIG1 involves the PI3K/Akt pathway in ovarian cancer cells.
Interferon-gamma (IFN-gamma) is known to downregulate HER2 oncoprotein (p185(HER2) or briefly p185) in prostate cancer cells. We demonstrate that the IFN-gamma-induced retinoid-inducible gene 1 (RIG1) acts as a transrepressor of p185. Furthermore, we exhibit that RIG1 downregulates the activated (phosphorylated) form of p185 and phosphoinositide-3 kinase (PI3K)/serine/threonine-specific protein kinase (Akt) and the mammalian target of rapamycin (mTOR), downstream substrates of HER2. We also elucidate that heregulin (HRG) specifically restores the activation of p185 and Akt after their activities are reduced by RIG1. Additionally, expression of vascular endothelial growth factor (VEGF) increases through the HER2- and Akt/mTOR-signaling pathways, indicating that VEGF is downregulated by RIG1 within the cell. These findings suggest that RIG1 plays a role in IFN-gamma-mediated therapy by downregulating p185 and its downstream PI3K/Akt/mTOR/VEGF-signaling pathway. These results may provide a new therapeutic mechanism for the clinical use of IFN-gamma and RIG1.
Ou
Chien-Chih
CC
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 114, Republic of China.
Hsu
Shih-Chung
SC
Hsieh
Yin-Hui
YH
Tsou
Wan-Ling
WL
Chuang
Tzu-Chao
TC
Liu
Jah-Yao
JY
Kao
Ming-Ching
MC
D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008954:Models, Biological; D020890:Neuregulin-1 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis*; D015398:Signal Transduction
D007371:Interferon-gamma; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018168:Receptors, Retinoic Acid; C437968:PLAAT4 protein, human; C508053:ERBB2 protein, human