Tuskegee University Cancer Research Center
The Cancer Research Program at Tuskegee University is carried out in partnership with the University of Alabama at Birmingham and the Morehouse School of Medicine. The research focus at Tuskegee University is prostate cancer. The program includes cancer research, education, research training, career development, and outreach.
In Vitro Analysis of Prostate Tumor Inhibition by LHRH Analogs
At the time of diagnosis, more than half of prostate tumors have invaded and metastasized. Early detection of prostate cancer is not a fail-safe cure since the tumors can quickly attain hormone-independence. Thus, it is imperative that we understand the biology of tumor growth regulation to define new therapeutic targets. Luteinizing hormone releasing hormone (LHRH) and its analogs directly inhibit growth of human, androgen-independent prostate cell lines, including DU-145. The mechanism by which these analogs exert their antiproliferative effects is unknown. We propose that LHRH analogs limit the pro-growth signaling through the epidermal growth factor receptor (EGFR).
Previously we have shown that:
- DU-145 cells growth and invasion are mediated through the EGFR, and
- EGFR-signaled cell responses are subject to PKC-mediated negative transmodulation by direct phosphorylation of the EGFR
Although the data on LHRH signaling in prostate cells is still uncertain, LHRH agonists stimulate phospholipase-C (PLC) activity in mammary tumors in a similar manner as LHRH does in the pituitary gland. Our model has PLC activity generating diacylglycerol (DAG) and mobilizing intracellular Ca2+ to activate protein kinase C (PKC). These findings lead us to hypothesize that the antiproliferative effects of LHRH agonists are mediated through negative attenuation of the EGFR, which is inactivated by phosphorylation by PKC.
We propose to elucidate LHRH signaling mechanism for inhibition of cell proliferation and invasion in DU-145 cells under in vitro conditions utilizing potent LHRH analogs. Our specific aims for this study are to determine whether LHRH analogs:
- prevent prostate tumor growth and/or invasion and progression in vitro
- influence cell adhesion profile
- achieve their effects via PKC-mediated transmodulation
- alter the telomerase expression profile
The successful completion of this project will elucidate the intracellular mechanism by which LHRH analogs exert their antiproliferative effect. This will identify intracellular pathways whose disruption hold promise for restricting prostate cancer progression.
Cancer Research News
Video used with permission