The transcription factor nuclear factor kappaB (NF-kappaB) has been linked to acquired therapeutic resistance in multiple types of human cancer by inhibiting cell death and drug sensitivity of malignant cells. Various genotoxic agents used in cancer treatment, such as chemotherapeutic drugs and irradiation, have been shown to activate NF-kappaB, which is a major impediment to effective cancer treatment. Our long term goal is to improve efficacy of radio/chemotherapy and reduce the resistance of cancer cells by modulating the genotoxic NF-kappaB signaling pathway. Our previous studies established a conserved nuclear-to-cytoplasmic signaling pathway which orchestrates NF-kappaB activation induced by a broad range of genotoxic therapeutic agents. We found ELKS (a protein rich in glutamate, leucine, lysine and serine) is indispensable for the activation of IKK complex and NF-kappaB by genotoxic agents. Our preliminary studies indicate posttranslational modifications of ELKS, such as ubiquitination and phosphorylation, orchestrate the process of ATM-dependent IKK activation, resulting in NF-kappaB activation in response to genotoxic therapeutic agents. Genetic ablation of ELKS significantly increases the mortality in mice exposed to ionized radiation. We hypothesize that DNA damage-induced ELKS posttranslational modifications play critical roles in genotoxic NF-kappaB signaling pathway, and modulating genotoxic NF-kappaB activation may sensitize tumor cells to genotoxic agent-induced cell death. We will test the hypothesis with the following specific aims:
Aim 1 is to characterize the ubiquitination of ELKS in genotoxic NF-kappaB signaling pathway.
In aim 2, we will delineate how ATM regulates ELKS ubiquitination induced by genotoxic stress. We will further determine biological functions of ELKS mediated DNA damage response and its impact on therapeutic resistance in vivo in Aim3. Completion of the proposed specific aims outlined in this grant proposal will advance our understanding of the molecular mechanism governing the ELKS-mediated genotoxic NF- kappaB signaling and its function in regulating therapeutic resistance. Furthermore, the exploration of the non-neuronal function of ELKS and potential cytoplasmic activity of ATM may reveal novel research paradigm which may greatly broaden our knowledge in the physiological and pathological functions of these important molecules. We envision the selective inhibition of NF-kappaB activity by targeting specific signaling mechanisms will effectively alleviate the therapeutic resistance while keeping immune response intact in cancer patients.

Public Health Relevance

One of the major obstacles to effective cancer treatment is the development of therapeutic resistance by cancer cells, which may lead to recurrence of the cancer or even death of the patient. By elucidating molecular mechanisms and biological functions of the signaling pathways helping cancer cells evade from demise induced by tumor therapeutic agents, the present studies will provide insights into how these agents induce therapeutic resistance in malignant cells, which will lead to novel strategies for improving the efficacy of cancer treatment through sensitizing tumor cells to chemotherapy and irradiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149251-02
Application #
8206626
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$307,100
Indirect Cost
$99,600
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Niu, Jixiao; Shi, Yuling; Tan, Guangyun et al. (2012) DNA damage induces NF-ýýB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion. J Biol Chem 287:21783-95
Niu, Jixiao; Shi, Yuling; Iwai, Kazuhiro et al. (2011) LUBAC regulates NF-ýýB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. EMBO J 30:3741-53