Researchers at the Johns Hopkins Kimmel Cancer Center have for the first time implicated the muscle protein myosin VI in the development of prostate cancer and its spread.
In a series of lab studies with human prostate cancer cells, the Hopkins scientists were surprised to find overproduction of myosin VI in both prostate tumor cells and precancerous lesions. When the scientists genetically altered the cells to "silence" myosin VI, they discovered the cells were less able to invade in a test tube.
"Our results suggest that myosin VI may be critical in starting and maintaining the malignant properties of the majority of human prostate cancers diagnosed today," says Angelo M. De Marzo, M.D., Ph.D., a study coauthor and associate professor of pathology, urology and oncology.
The Hopkins work, published in the November issue of the American Journal of Pathology, has potential value for better ways to diagnose the disease, treat and track the effects of drugs and surgery. "Targeting myosin VI represents a promising new approach that could lead eventually new approaches to treating the disease," says Jun Luo, Ph.D., senior author of the paper and assistant professor of urology.
Myosins are a class of 40 motor proteins that power cell movement and muscle contractions. Normally, as they work, myosins slide in a single direction along the threads of a protein called actin. But myosin VI moves against the grain, and it does not function as a classical "muscle" protein.
Using a DNA microarray to study all of the genes in 59 samples of benign or cancerous prostate tissue from patients at Johns Hopkins, the researchers found the malignant samples showed a 3.7-fold higher expression of myosin VI as compared to normal samples, and a 4.6-fold increase as compared to the samples from patients with enlarged prostate.
Next, the researchers hunted for myosin VI in 240 prostate tissue samples, discovering overproduction early in the development of prostate cancer in such pre-tumor conditions as high-grade prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy.
Finally, when they altered some cancerous cells by knocking down their myosin VI protein, the cancer cells not only were less able to spread around, but also showed 10 times the amount of a tumor suppressor called thioredoxin-interacting protein (TXNIP).
Prostate cancer, which affects one in nine American men over the course of their lives, is mainly diagnosed by needle biopsy of the prostate gland after a blood test shows an increased level of prostate-specific antigen (PSA). While the PSA test is now widespread and provides many men with early diagnosis and better chance of a cure, says Luo, it may not be sensitive or specific enough to pinpoint the existence of cancer. Using myosin VI or other factors, it may be possible, Luo says, to create a laboratory test to identify high or low levels in urine or blood samples, and this might aid in the detection of prostate cancer. Myosin VI also has been shown to be associated with ovarian cancer.
The study was supported by the U.S. Department of Defense, the National Cancer Institute, the Donald and Susan Sturm Foundation and the Prostate Cancer Foundation. Coauthors were Thomas A. Dunn, Shenglin Chen, Dennis A. Faith, Jessica L. Hicks, Elizabeth A. Platz, Yidong Chen, Charles M. Ewing, Jurga Sauvageot and William B. Isaacs.
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