Study finds AKT blocks cancer cell motility; paradoxical discovery raises questions in developing cancer inhibitor therapies
BOSTON – In 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 blocks 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."
In other words, he says, while a majority of cancer cells will die, those that are able to escape death will be left with a far stronger ability to metastasize and spread to other parts of the body.
"This paper is important because it shows that a pathway known to be involved in initiating breast cancer, the PI3K/AKT pathway, also plays a paradoxical role in suppressing the ability of the tumor to invade new tissues," says Lewis Cantley, PhD, director of the division of signal transduction at BIDMC and professor of systems biology at HMS, in whose laboratory the PI3K pathway was first discovered. "This new discovery suggests that tumors that result from activation of the PI3K/AKT pathway are unlikely to be metastatic unless another mutation occurs to circumvent the block on invasion. The results also suggest that the status of the NFAT pathway that is implicated in invasion should be evaluated in breast tumors."
The study also points out the extremely complex nature of cancer cell pathways.
"We now know that AKT has very different – even competing – functions in its dual roles as both a survival kinase and a motility kinase," says Toker. "In terms of developing future therapies, this poses a host of new questions and challenges and above all, indicates that much more work is needed to arrive at a comprehensive picture of the role of AKT in cancer before it can be targeted for therapeutic purposes."
Study coauthors include BIDMC investigators Merav Yoeli-Lerner, PhD, Gary K. Yiu, PhD, and Isaac Rabinovitz, PhD; Peter Erhardt, PhD, of the Boston Biomedical Research Institute; and Sebastien Jauliac, Ph.D., of Hopital Saint-Louis, Paris, France.
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