Date of Award

7-1-2013

Degree Type

Dissertation

University or Center

Clark Atlanta University(CAU)

School

School of Arts and Sciences

Degree Name

Ph.D.

Department

Biology

Biological Sciences

First Advisor

Dr. Cimona V. Hinton

Second Advisor

Dr. Shafiq A. Khan

Third Advisor

Dr. Anita H. Corbett

Abstract

The G-protein coupled receptor (GPCR) Cysteine (C)-X-C Receptor 4 (CXCR4) plays an important role in prostate cancer metastasis. CXCR4 is regarded as a plasma membrane receptor, that it transmits signals that support transformation, progression and metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutic approaches such as antagonists and monoclonal antibodies have focused on receptors the located at the plasma membrane. An emerging concept for GPCRs is that they can localize to the nucleus where they may retain function and mediate nuclear signaling. Herein, we demonstrate that CXCR4 is highly expressed in high grade metastatic prostate cancer tissues. Increased expression of CXCR4 is also detected in several prostate cancer cell lines as compared to normal prostate epithelial cells. Our studies identify a nuclear pool of CXCR4 and also define a mechanism for nuclear targeting of CXCR4. A classical nuclear localization sequence (cNLS), "RPRK", in CXCR4 can contribute to nuclear localization. In addition, CXCR4 interacts with the nuclear transport receptor, Transportin βi, to promote nuclear accumulation of CXCR4. Importantly, Gαi immunoprecipitation and calcium mobilization studies indicate that nuclear CXCR4 is functional and can participate in G-protein signaling revealing that the nuclear pool of CXCR4 can retain function. Localization of functional CXCR4 to the nucleus may be a mechanism by which prostate cancer cells evade treatment, thus contributing to increased metastatic ability and poorer prognosis after tumors have been treated with therapy that targets plasma membrane CXCR4. This study addresses the mechanism of nuclear targeting for CXCR4 and demonstrates that CXCR4 can retain function within the nucleus and provides important new information to illuminate what have previously been primarily clinical observations of nuclear CXCR4.

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