Prostate cancer (PCa) is the most common cancer among men. Although androgen deprivation has been a major therapy for advance PCa patients, it inevitably becomes ineffective once the cancer transforms to hormone resistant. In order to design better therapeutic strategies, intensive research effort has focused on the identification of novel molecular targets. It is known that the enhanced activation of the mitogen-activated protein kinase (MAPK) Raf-MEK-ERK pathway is correlated with the progression, androgen independence and poor prognosis of PCa and thus, the signaling molecules involved in the regulation of this pathway have been thought to be suitable targets for therapeutic intervention. However, the molecular mechanisms underlying the hyper-activation of Raf-MEK-ERK pathway in PCa remain poorly defined. Despite the fact that multiple genetic mutations have been identified in receptor tyrosine kinases, Ras, Raf and MEK which largely contribute to the elevated activation of the MAPK pathway in many types of malignancies, these mutations are infrequent in PCa patients. The goal of this application is to reveal oncogenic actions of ADP-ribosylation factor 1 (ARF1) via activating the MAPK pathway in PCa cells and explore ARF1-mediated signaling as a novel therapeutic target for prostate tumorigenesis. Our preliminary studies have demonstrated for the first time that ARF1 is a potent oncogene which significantly contributes to the elevated activation of the MAPK pathway and the progression of PCa. The central hypothesis of this proposal is that ARF1-mediated Golgi-associated activation of the MAPK pathway plays a crucial role in prostate tumorigenesis and targeting it will prevent PCa progression. There are three Specific Aims in the proposal.
Specific Aim 1 will test the hypothesis that oncogenic G protein-coupled receptors activate ARF1 via the translocation of G?? subunits to the Golgi in PCa cells.
Specific Aim 2 will test the hypothesis that the Golgi apparatus spatially provides a platform upon which ARF1 activates the MAPK pathway via a direct interaction with Raf1 in PCa cells.
Specific Aim 3 will test the hypothesis that ARF1 inhibitors effectively suppress prostate cancer progression. Overall, this project will reveal previously unrecognized functions of ARF1 in PCa biology and explore a novel means to inhibit the tumorigenesis of PCa by targeting ARF1-mediated Golgi-associated oncogenic signaling. These studies will directly impact the future development of effective therapy for PCa patients.

Public Health Relevance

This proposal will define the novel molecular mechanisms that govern the activation of the mitogen-activated protein kinase pathway in prostate cancer and identify small molecules that inhibit the prostate tumorigenesis. The successful completion of these studies will directly impact the future development of effective therapy for prostate cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
High Priority, Short Term Project Award (R56)
Project #
5R56CA204315-02
Application #
9539979
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Espey, Michael G
Project Start
2017-08-01
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Augusta University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Li, Chunman; Wei, Zhe; Fan, Yi et al. (2017) The GTPase Rab43 Controls the Anterograde ER-Golgi Trafficking and Sorting of GPCRs. Cell Rep 21:1089-1101