title: Loss of compensatory pro-survival and anti-apoptotic modulator, IKKε, sensitizes ovarian cancer cells to CHEK1 loss through an increased level of p21.
abstract: Ovarian cancer (OC) is extremely heterogeneous, implying that therapeutic strategies should be specifically designed based on molecular characteristics of an individual's tumor. Previously, we showed that IKKε promotes invasion and metastasis in a subset of OCs. Here, we identified CHEK1 as an IKKε-dependent lethal gene from shRNA kinome library screen. In subsequent pharmacological intervention studies, the co-inhibition of IKKε and CHEK1 was more effective in killing OC cells than single treatment. At the molecular level, co-inhibition dramatically decreased pro-survival proteins, but increased proteins involved in DNA damage and apoptosis. IKKε-knockdown increased p21 levels, while overexpression of wild-type IKKε, but not a kinase dead IKKε mutant decreased p21 levels. We further demonstrated that the depletion of p21 rendered OC cells more resistant to cell death induced by co-inhibition of IKKε and CHEK1. In conclusion, we revealed a novel interplay between IKKε, CHEK1 and p21 signaling in survival of OC. Our study provides a rationale for the clinical development of specific IKKε inhibitor and for usage of IKKε as an exploratory marker for resistance to CHEK1 inhibitors in the clinic. The interplay provides one potential explanation as to why very few clinical responses were achieved in patients treated with single-agent CHEK1 inhibitors.
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Transgenic Oncogenic and Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Dong J
authors.initials: DJ
authors.lastname: Min
authors.affiliation: Biometrics Research Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.affiliation: NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD 20892.
authors.forename: Ian
authors.initials: I
authors.lastname: Goldlust
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D051550:I-kappa B Kinase