Downregulation of HER2 by RIG1 involves the PI3K/Akt pathway in ovarian cancer cells

Abstract

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.

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

“…These observations are consistent with previous findings showing that RARRES3 suppresses cell proliferation and triggers cell apoptosis by interfering with the c-Jun N-terminal kinases (JNK), ERK and PI3K/Akt pathways. 34,35 However, activation of these pathways is significant in RARRES3-silenced cells (Supplementary Figure S2), suggesting that the RARRES3 expression level is critical for the regulation of cell growth and survival signaling.…”

“…Consistently, previous studies have shown that acylation is required for Wnt proteins to be transported to the PM. 20,22 As RARRES3 extensively suppresses diverse growth signaling in many tumor cells, 34,35 it is likely that RARRES3 exerts its protein deacylation role on other growth-signaling pathways. For example, it has been reported that RARRES3 co-localizes with and restrains H-Ras in the Golgi apparatus.…”

“…34 Most cell proliferation signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK) and the small GTPase H-Ras, have been shown to be suppressed in RARRES3-overexpressing cells. 34,35 In addition, RARRES3 has recently been shown to display phospholipase PLA 1/2 and acyltransferase activities in in vivo and in vitro studies. 36,37 Furthermore, previous studies on the tumorsuppressive effect of RARRES3 focused primarily on the characterization of its functional domains and its physiological targets, while few reports have investigated the implications of its enzymatic activity.…”

“…34,35,38 In addition, the deregulation of Wnt/β-catenin signaling leads to abnormal cell proliferation and metastatic activity, which is frequently found in human breast cancer cells. In the present study, we demonstrate that RARRES3 exerts a remarkable effect on the acylation level of Wnt/β-catenin signaling molecules and therefore inhibits the tumorous growth and stemness properties of breast cancer cells.…”

Resistance to chemotherapy and hormone therapy in endometrial cancer

“…HER2 is a transmembrane receptor, which is encoded by the c-erbB2 gene located on chromosome 17. The important intracellular signaling pathways activated by HER2 include PIP3 and the AKT pathway (Ou et al 2008). EGFR and HER2 gene polymorphisms in endometrial cancer has also been reported (Kitao et al 2007) but the clinical significance of these polymorphisms has yet to be identified.…”