Researchers Uncover How Prostate Cancer Cells Defy Death

"We hope this will lead to new treatments or ways to monitor treatment to make sure it's having its intended effect," said George Kulik, Ph.D., D.V.M., assistant professor of cancer biology and senior researcher.

The goal of the research was to uncover how prostate cancer cells become resistant to treatment that lowers levels of male hormones such as testosterone, which the cells normally need to survive. They found that a protein known as BAD is involved in three different survival strategies used by the cancer cells. Their results are published in the July 28th issue of the Journal of Biological Chemistry.

"The normal response of prostate cells when male hormones are blocked is cell death," said Kulik. "The cancer cells find a way to resist the treatment and we wanted to discover the mechanism."

Treatments for prostate cancer include surgery, radiation therapy and hormone therapy, also known as androgen ablation therapy because it reduces levels of the male hormones that can stimulate the growth certain types of prostate cancer. Lowering hormone levels makes prostate cancer shrink or grow more slowly. It is considered the most efficient systemic therapy for prostate cancer. However, nearly all prostate cancers become resistant to this treatment over time.

The researchers evaluated three different pathways involved in cell signaling, the complex system of communication that governs cell actions. It had previously been shown that three pathways (activated by vasoactive intestinal peptide, epidermal growth factor or phosphoinositide 3-kinase) are known to be involved in cell survival. The goal of the researchers was to learn how these pathways are involved in the cancer cells resisting death. They found that all three signaling pathways work by inactivating a protein known as BAD that causes cell death.

Kulik said it appears that each of the three molecules is separately capable of inactivating BAD, which means that prostate cancer cells have three redundant survival mechanisms.

"Our findings suggest that BAD is an important switch in the development and growth of prostate cancer," said Kulik.

Next, the researchers hope to conduct animal studies to test their findings.

"If our finding is confirmed in animals and in human tumors, there are important implications for therapy," said Kulik.

For example, scientists could develop a drug to prevent BAD from being inhibited. Or, they could use the findings to test current drugs designed to block the effects of PI3K, one of the molecules. This would involve monitoring the status of BAD to see if the drugs were having their intended effects.

According to the American Cancer Society, prostate cancer is the most common type of cancer found in American men, other than skin cancer. The society estimates that there will be about 234,460 new cases of prostate cancer in the United States in 2006. About 27,350 men will die of this disease. Prostate cancer is the third leading cause of cancer death in men, after lung cancer and colorectal cancer.

Funding for the study included grants from the Department of Defense and the Comprehensive Cancer Center of Wake Forest University Baptist Medical Center.

Co-researchers were Konduru Sastry, Ph.D., Adrienne Joy Smith, B.S., Yelena Karpova, B.S., all with Wake Forest, and Sandeep Datta, M.D., Ph.D., with Columbia University.