NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. NEDD4-1 plays an important role in tumorigenesis. Although it has been suggested that NEDD4-1 functions as an oncogenic protein by facilitation of Akt activation, the molecular mechanisms by which NEDD4-1 activates Akt remain largely unknown. We found that NEDD4-1 activates Akt via regulation of IGF-1R signaling. Strikingly, we also found that activation of Akt by NEDD4-1 is negatively regulated by replication protein A (RPA), a single strand DNA (ssDNA) binding protein which is generally believed to play a critical role in DNA metabolism. Thus, we are proposing a study to test the central hypothesis that NEDD4-1 plays a role in cell proliferation via activation of IGF-1R signaling and this pathway is inhibited by RPA. Therefore, growth of cells overexpressing NEDD4-1 is specifically suppressed by IGF-1R inhibition through IGF-1R antibody and/or RPA. Three interrelated specific aims are proposed to test our hypothesis.
Aim 1 will identify the role of NEDD4-1 in cell proliferation via regulation of IGF-1R signaling.
Aim 2 will delineate how NEDD4-1 dependent IGF-1R signaling is regulated by RPA.
Aim 3 will determine the antitumor activity of blocking IGF-1R signaling in cells over-expressing NEDD4-1. We anticipate to (1) define the molecular mechanisms by which NEDD4-1 promotes cell proliferation via regulation of IGF-1R signaling;(2) identify a novel function of RPA in suppression of IGF-1R signaling via interaction with NEDD4-1;(3) find that the growth of cancer cells over-expressing NEDD4-1 can be specifically targeted by IGF-1R inhibition through RPA and/or IGF-1R antibody. The expected results will fundamentally advance our understanding of the molecular mechanism underlying NEDD4-1 associated cancer development. In addition, identification of a novel function of RPA in suppression of IGF-1R signaling will facilitate the development of novel drugs targeting NEDD4-1 or IGF-1R. Moreover, the expected result will improve guidance for cancer treatment plans based on better predictions of tumor response to IGR-1R inhibition by identification of cancer patients with NEDD4-1 over-expression.

Public Health Relevance

NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. Our proposed studies are aimed at delineating the role of NEDD4-1 in cell proliferation and cancer therapy via regulation of IGF-1 receptor (IGF-1R). The successful completion of this work would (1) advance cell signaling field by providing mechanistic insight into NEDD4-1 associated cancer development;(2) facilitate the identification and development of biomarkers and drug targets in human cancer;(3) provide new guidelines and novel approaches for treating cancer patients with NEDD4-1 over-expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154625-03
Application #
8316173
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
2011-08-08
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$325,775
Indirect Cost
$118,275
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106