Abstract
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.
Highlights
Ovarian cancer is the eighth most common cancer among women and the most lethal gynecological cancer, and an estimated 239,000 new cases and 152,000 deaths were reported worldwide in 20121
We demonstrated that an orphan receptor tyrosine kinase TIE-1 up-regulates xeroderma pigmentosum complementation group C (XPC)-dependent nucleotide excision repair (NER) rendering ovarian cancer cells resistant to platinum reagents and is a key determinant responsible for the therapeutic efficacy of DNA-damaging reagents in ovarian cancer by controlling a DNA repair system
Numerous genes have been implicated in platinum resistance, such as multidrug resistance protein 2 (MRP2) involved in cisplatin efflux[7], glutathione and metallothionein involved in platinum detoxification[8], and excision repair cross-complementation group 1 (ERCC1) involved in DNA damage repair[10]
Summary
Ovarian cancer is the eighth most common cancer among women and the most lethal gynecological cancer, and an estimated 239,000 new cases and 152,000 deaths were reported worldwide in 20121. Cell viabilities of cisplatin-treated (y-axis) and untreated (x-axis) cells relative to control siRNA treatment were shown. A2780CP cells plated on glass bottom 35 mm dishes were transfected with control or TIE-1 siRNAs for 24 h and treated with 10 μM cisplatin or PBS for 12 h. The numbers of γH2AX positive cells were counted and the results are representative of three independent experiments (H). Values represent the mean ± SD. *P < 0.05
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