Cellular molecule spurs growth of prostate cancer

November 29, 2005

CHAPEL HILL - University of North Carolina at Chapel Hill scientists have identified a molecule that stimulates the aggressive growth of prostate cancer. The molecule, Ack1, a member of the growth-promoting tyrosine kinase gene family, stimulates tumor formation in part by signaling prostate cells to rid themselves of a tumor-suppressor protein. Normally, this suppressor protein would inhibit rapid cell growth by signaling the cell to destroy itself.

A report on the study, which appeared Nov. 15 in the journal Cancer Research, also points to Ack1 as a potential target for developing novel drugs against prostate cancer.

The study's senior author, Dr. Shelton Earp, directs the UNC Lineberger Comprehensive Cancer Center and is Lineberger professor of cancer research and a professor of pharmacology and medicine.

Tests of Ack1 demonstrate a profound effect on tumor growth in experimental systems, Earp said. "It's a remarkable effect. Tumors grew more rapidly and invaded as if they were converted to advanced prostate cancer."

Another major finding of the study involved an experimental drug developed by the National Cancer Institute, called geldanamycin. In laboratory tests, the UNC Lineberger group found Ack1 activity could be inhibited through interference with its molecular interactions, thus offering a target for treatment. First, the group discovered that Ack1 bound to a protein called Hsp90 (heat shock protein 90), which associated with many oncogenic, or cancer-causing, signaling proteins.

"If you add geldanamycin to the prostate cancer cell, the drug knocks Hsp90 off oncogenic signaling molecules. This dramatically decreases Ack1 activity and slows tumor formation," Earp said.

In addition, the team compared Ack1 activation in advanced prostate cancer tissue from patients with that found in benign prostatic hypertrophy, or non-cancerous prostate enlargement. The team showed the levels of the activated Ack1 to be much higher in the advanced tumors.

In earlier work, Earp's UNC laboratory was the first to clone a cell surface tyrosine kinase, Mer.

"We saw that Mer was expressed at reasonably high levels in prostate cancer cells. And so Dr. Nupam Mahajan, the study's first author, decided to look at whether Mer had an effect on prostate cancer growth signaling," Earp said.

In experiments, which used the university's Michael Hooker Proteomics Core Facility, the team discovered that Mer activated Ack1. This finding led to the current study.

"Because we found Ack1 is more active in advanced prostate tumors, and its inhibition blocks experimental tumor growth, we believe Ack1 should be a target for novel drug development."
-end-
Along with Earp, UNC collaborators include UNC Lineberger members Dr. Nupam P. Mahajan, assistant professor of pharmacology; and Dr. Young E. Whang, assistant professor of medicine. Dr. James L. Mohler, chairman of the department of urologic oncology at Roswell Park Cancer Institute in Buffalo, N.Y., and a UNC Lineberger member, also collaborated on the study.

The research was funded by the National Cancer Institute.

By LESLIE H. LANG
UNC School of Medicine

UNC Lineberger contact: Dianne Shaw, (919) 966-7834 or dgs@med.unc.edu
UNC School of Medicine contact: Les Lang, (919) 843-9687 or llang@med.unc.edu

University of North Carolina Health Care

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