TY - JOUR
T1 - Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer
AU - Ishibashi, Masumi
AU - Toyoshima, Masafumi
AU - Zhang, Xuewei
AU - Hasegawa-Minato, Junko
AU - Shigeta, Shogo
AU - Usui, Toshinori
AU - Kemp, Christopher J.
AU - Grandori, Carla
AU - Kitatani, Kazuyuki
AU - Yaegashi, Nobuo
N1 - Funding Information:
This study was supported in part by the NIH Grant UO1 CA176303 (to C.K.) and the JSPS Grants-in-Aids for Scientific Research (16K11125 to K.K., 24390375 to N.Y. and 26462509 to M.T.). We also thank the laboratory members of the Departments of Obstetrics and Gynecology (Tohoku University, Sendai) for critical discussion. We are grateful to Drs. Shunsuke Kayamori and Yuki Furuuchi and the laboratory member of the Technical Division, School of Engineering (Tohoku University, Sendai) for significant support in Atomic Absorption Spectrometry.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053014821&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053014821&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-31069-2
DO - 10.1038/s41598-018-31069-2
M3 - Article
C2 - 30181600
AN - SCOPUS:85053014821
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 13207
ER -
