Abstract
Tyrosine kinase receptor TIE-1 plays a critical role in angiogenesis and blood-vessel stability. In recent years, increased TIE-1 expression has been observed in many types of cancers; however, the biological significance and underlying mechanisms remain unknown. Thus, in the present study, we investigated the tumor biological functions of TIE-1 in ovarian cancer. The treatment of SKOV3 ovarian-cancer cells with siRNA against TIE-1 decreased the expression of key molecules in the PI3K/Akt signaling pathway, such as p110α and phospho-Akt, suggesting that TIE-1 is related to the PI3K/Akt pathway. Furthermore, the knockdown of TIE-1 significantly decreased cell proliferation in high-PI3K-expressing cell lines (SKOV3, CAOV3) but not low-PI3K-expressing cell lines (TOV112D, A2780). These results suggested that inhibition of TIE-1 decreases cell growth in high-PI3K-expressing cells. Moreover, in low-PI3K-expressing TOV112D ovarian-cancer cells, TIE-1 overexpression induced PI3K upregulation and promoted a PI3K-mediated cell proliferative phenotype. Mechanistically, TIE-1 participates in cell growth and proliferation by regulating the PI3K/Akt signaling pathway. Taken together, our findings strongly implicate TIE-1 as a novel therapeutic target in high-PI3K-expressing ovarian-cancer cells.
Highlights
Ovarian cancer is a highly lethal global gynecologic malignancy [1,2]
To determine the biological functions of tyrosine kinase receptor TIE-1, we introduced TIE-1 knockdown using siRNA and measured the expression of key proteins in the Phosphoinositide 3-kinases (PI3Ks)/Akt signaling pathway
Immunoblotting analysis showed that TIE-1 knockdown significantly suppressed the protein expression of PI3K p110α and phospho-Akt, with no change in total Akt (Figure S1), in SKOV3 ovarian cancer cells (Figure 1A–C)
Summary
Ovarian cancer is a highly lethal global gynecologic malignancy [1,2]. Most patients are diagnosed at an advanced stage, and the five-year survival rate is in the range of 30–40% [3]. ovarian-cancer cells are sensitive to platinum-based chemotherapy, recurrence and the development of drug resistance make ovarian cancer difficult to treat [4]. Ovarian cancer is a highly lethal global gynecologic malignancy [1,2]. Most patients are diagnosed at an advanced stage, and the five-year survival rate is in the range of 30–40% [3]. The establishment of novel therapeutic strategies for refractory ovarian cancer is an urgent need. Tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE)-1 is a cell-membrane protein expressed in endothelial cells [5,6]. TIE-1 is considered an orphan receptor far [7,8], recently LECT2, a functional ligand of TIE-1, has been reported [9]. Xu and colleagues showed that LECT2/TIE-1 signaling pathway promotes liver fibrogenesis; the significance
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