Platinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.

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.