Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer.
I-kappa-B kinase e (IKBKE; IKKepsilon) has been recently identified as a breast cancer oncogene, and its alteration appears to be an early event in breast cancer development. In this study, we demonstrated that IKKepsilon is frequently overexpressed and activated in human ovarian cancer cell lines and primary tumors. Of 96 ovarian cancer specimens examined, 63 exhibited elevated levels of IKKepsilon. Furthermore, alterations of IKKepsilon were associated with late-stage and high-grade tumors, suggesting a role of IKKepsilon in ovarian tumor progression rather than in tumor initiation. Overall survival in patients with elevated levels of IKKepsilon was significantly lower than patients whose tumors expressed normal levels of IKKepsilon. Moreover, both early and late-stage tumors that overexpressed IKKepsilon conferred a poor prognosis, as compared with those that did not possess elevated IKKepsilon levels. Notably, overexpression of IKKepsilon rendered cells resistant to cisplatin, whereas knockdown of IKKepsilon overcame cisplatin resistance in both A2780CP and C13 cells, which express high levels of endogenous IKKepsilon. Therefore, these data demonstrate for the first time that deregulation of IKKepsilon is a highly recurrent event in human ovarian cancer and could play a pivotal role in tumor progression and cisplatin resistance. IKKepsilon could also serve as a prognostic marker and potential therapeutic target for this malignancy.
Guo
Jian-Ping
JP
Departments of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
Shu
Shao-Kun
SK
He
Lili
L
Lee
Yi-Chun
YC
Kruk
Patricia A
PA
Grenman
Seija
S
Nicosia
Santo V
SV
Mor
Gil
G
Schell
Michael J
MJ
Coppola
Domenico
D
Cheng
Jin Q
JQ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D015139:Blotting, Southern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; D002945:Cisplatin