PIn investigating the molecular mechanisms of cancer cell motility - the unique property that enables cancer to spread from its primary origin to other parts of the body - researchers have uncovered a surprising role for the AKT/PKB (protein kinase B) enzyme, providing important new insights into cancer metastasis and suggesting that current efforts to develop cancer therapies by inhibiting AKT may be inadvertently promoting the spread of the disease.
Led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) and described in a study in the Nov. 23 issue of the medical journal Molecular Cell, the research demonstrates for the first time that AKT, which is known to increase cancer cells' survival capability also paradoxically increases their motility and invasion abilities, thereby preventing cancer from spreading.
"The aggressive behavior of malignant cancer cells is determined by a complex array of signaling pathways that regulate key functions including cell proliferation, survival capacity, and the ability to migrate from their original location and invade other regions of the body," explains the study's senior author Alex Toker, Ph.D., a member of the department of pathology at BIDMC and associate professor of medicine at Harvard Medical School.
In the 1990s AKT, a component of the phosphoinositide 3-kinase (PI3K) signaling pathway, was first found to promote cancer cells' survival capacity, and since then the enzyme has also been shown to control cell proliferation.
"In essence, cancer cells have highjacked this enzyme and its regulatory proteins in order to increase their ability to survive," explains Toker. "By blocking the pathway - and thereby causing cell death -- AKT has become a popular target in the development of cancer inhibitor drugs."
Although cell migration is an essential feature of the invasive phenotype of cancer cells, relatively little information has been available on AKT's role in this key function. As a result, the discovery that this kinase actually blocks cancer cell motility and invasion was totally unexpected. "We asked ourselves, 'how is this happening?'"says Toker.
The answer, he explains, may lie in a discovery made in his laboratory in 2002, when a transcription factor known as NFAT was identified in aggressive carcinomas of the breast and colon. (Until that point, NFAT was primarily known for its role in providing the body's immune system with a line of defense against infection.)
"Our new findings suggest that it is an NFAT-dependent mechanism that is allowing AKT to block cancer cell motility and subsequent invasion," explains Toker. "Earlier animal studies have shown that although tumors are more likely to develop in the mammary tissue of mice expressing excessive AKT, these animals actually develop fewer metastatic lesions than do control mice. Taken together with our new findings, these results suggest that by inhibiting AKT, not only do you block cancer survival, you also increase cells' properties of motility and invasiveness."