Oncotarget

Research Papers:

Loss of compensatory pro-survival and anti-apoptotic modulator, IKKε, sensitizes ovarian cancer cells to CHEK1 loss through an increased level of p21

Marianne K. Kim _, Dong J. Min, George Wright, Ian Goldlust and Christina M. Annunziata

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Oncotarget. 2014; 5:12788-12802. https://doi.org/10.18632/oncotarget.2665

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Abstract

Marianne K. Kim1, Dong J. Min2, George Wright3, Ian Goldlust4, Christina M. Annunziata1

1Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

2Transgenic Oncogenic and Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

3Biometrics Research Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

4NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD 20892

Correspondence to:

Christina M. Annunziata, e-mail: annunzic@mail.nih.gov

Keywords: shRNAs, therapeutic targets, IKKε, CHEK1, p21, ovarian cancer

Received: October 02, 2014     Accepted: October 27, 2014     Published: November 15, 2014

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.


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