Role of alpha tocopherol associated protein in prostate cancer

Nov 1 2005

Researchers have identified a protein that disrupts an important signaling pathway in prostate cancer cells and suppresses growth of the cancer.

The protein also assists in the retention of vitamin E in prostate cancer cells and increases the effect of vitamin E in limiting the proliferation of cancer cells, the researchers found.

The researchers, led by ShuYuan Yeh, assistant professor of urology and pathology at the University of Rochester Medical Center, are the first to describe the role of a protein known as alpha tocopherol associated protein or TAP in prostate cancer. Expression levels of TAP are significantly lower in prostate cancer than in a normal prostate, the researchers found. High expression of TAP protein in prostate cells may have a physiological role in normal prostate development and vitamin E-related functions, Yeh said.

The findings are reported in the Nov. 1 issue of the journal Cancer Research.

Restoring TAP levels in men with prostate cancer could produce a therapeutic effect, but Yeh described the process as "difficult and limited." She and her research team are investigating whether specific substances can increase the expression of TAP.

While TAP itself someday could become an effective avenue of treatment for prostate cancer, it has immediate potential as a new prognostic marker.

"If research continues to show the important role of TAP, we could use TAP expression levels to better assess and predict the aggressiveness of the cancer," said urologist Edward M. Messing, M.D., chair of Urology at the University of Rochester Medical Center. "We may be able to use TAP levels to predict whether a patient will respond to treatment."

TAP is a binding protein that performs important cellular functions. In the liver, for example, TAP plays a role in regulating the synthesis of cholesterol.

Yeh and her research team found high levels of TAP in epithelial cells of normal prostate tissue. But in clinical human prostate cancer samples and in several tested prostate cancer cell lines, the researchers found TAP at significantly reduced levels.

The high levels of TAP in normal prostate cells suggest that TAP facilitates the transport of vitamin E into prostate tissue and helps retain high concentrations of the vitamin in the cells.

In prostate cancer cells, the researchers showed for the first time that TAP supports the retention of vitamin E. Yeh also found that TAP increases vitamin E's capacity to control the rapid growth of the cancer cells.

"Vitamin E and TAP have distinct pathways to modulate prostate cancer cell growth and we hypothesize that vitamin E and TAP can work together to elicit better tumor suppression effects," the researchers wrote in the Cancer Research article.

But Yeh also discovered that TAP by itself suppresses prostate cancer cell growth. A cell can send messages from its surface to the nucleus through a set of chemical reactions known as a signaling pathway. Yeh and her team identified a specific pathway disrupted by TAP. The disruption by TAP suppresses cancer cell growth.

The pathway involves two proteins, phosphatidylinositol 3-kinase and constitutively active Akt. "The pathway is very active in cancer, giving the cells a growth and survival advantage" Yeh said. "This pathway is not the only factor in prostate cancer, but it is an important one."

The Rochester researchers reintroduced TAP into the prostate cancer cells in the laboratory. They also injected mice with cancer cells and cancer cells with restored TAP.

"Reintroducing TAP expression in prostate cancer cells may have a therapeutic effect," Yeh said. "Proliferation of the cancer was reduced in cells with the reintroduced TAP. In mice with restored TAP, there was significantly reduced incidence of tumors and reduced size of tumors."

In addition to investigating which substances boost the expression of TAP, Yeh and the research group now are focusing on why, in prostate cancer, cells lose the capacity to express TAP.

"This research has great promise," Messing said. "Why is TAP expression low in cancer cells? Is it one of the things that drives cells to become malignant? If TAP expression is important, we might be able to interfere and restore TAP expression and affect the progress of the cancer."

The study was supported, in part, by a grant from the National Institutes of Health.

Yeh's research has focused on prostate cancer for several years. In an article in 2002 in the Proceedings of the National Academy of Sciences, Yeh and her research team showed that vitamin E interferes with two proteins that play a central role in the development of prostate cancer.

The researchers found then that vitamin E disrupts the ability of prostate cancer cells to make both prostate-specific antigen (PSA) and the androgen receptor, a key player in the development and progression of the disease.

"We know a lot more today about vitamin E because of Dr. Yeh's work," said Messing. "No one really knows how vitamin E works. TAP may give us insights into how vitamin E works anywhere in the body and why it is a required vitamin."

Messing heads the Rochester part of a national study designed to test whether either vitamin E or selenium, or a combination, prevents prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial is the largest clinical trial yet of prostate cancer preventives. Participants will be tracked for at least seven years, until about 2011.

After skin cancer, prostate cancer is the most common type of cancer in U.S. men. This year alone, there will be an estimated 232,000 new cases of prostate cancer and more than 30,000 U.S. deaths. Approximately one in six U.S. men will develop prostate cancer during his lifetime.

In addition to Yeh and Messing, other University of Rochester Medical Center authors on the article include Jing Ni, Xingqiao Wen, Jorge Yao, Yi Yin, Min Zhang, Shaozhen Xie, Ming Chen, Brenna Simons, Philip Chang, and Anthony di Sant' Agnese.