Cancer Resources > Cancer News > 2005 > December

Unexpected function of Akt could put the brakes on Akt inhibitors

Megan Rauscher

Last Updated: 2005-12-05 14:36:48 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Scientists have uncovered an unknown and unexpected role for the Akt/protein kinase B (PKB) cancer cell pathway. According to a report in the November 23rd issue of Molecular Cell, the Akt enzyme, which is known to promote survival of breast cancer cells, also paradoxically blunts the ability of breast cancer cells to migrate, thereby preventing cancer from spreading.

Therefore, blocking Akt "could increase invasion and metastasis of human breast and possibility other cancers," Dr. Alex Toker from Beth Israel Deaconess Medical Center in Boston warned in comments to Reuters Health. "We hope that this work will raise some caution for those who seek to block cancer spread using Akt inhibitors."

Since its discovery over a decade ago, the Akt/PKB pathway has been touted as an excellent candidate for cancer therapy. Akt is a pro-survival enzyme prevalent in cancer cells.

Recently, a number of promising small-molecule Akt inhibitors have been developed and, as predicted, some preliminary studies have shown that these Akt inhibitors effectively increase the death of cancer cells in the laboratory.

Using isolated breast cancer cells grown in the laboratory, Dr. Toker and colleagues confirmed that elevated Akt activity does indeed promote cancer cell survival but it also inhibits migration and invasion of breast cancer cells.

Conversely, downregulation of Akt activity using an inhibitor or some other genetic interference approach, results in a highly increased ability of cancer cells to migrate and invade.

"Target this enzyme with drugs and a substantial fraction of cells may indeed die," Dr. Toker said, "but those that escape this attack will have an increased propensity to invade the bloodstream and lymphatic systems, and ultimately metastasize to distant organs."

Akt blocks breast cancer cell motility and invasion, at least in part, by blocking the activity of a transcription factor called NFAT, according to the researchers. "Presumably, what NFAT does in cancer cells is to up-regulate the expression of genes which promote motility and invasion," Dr. Toker explained.

Dr. Toker said this research "once again reminds us of the immensely complex nature of molecular events which govern the behavior of cancer cells. Proteins such as Akt, which at first glance seemingly control only one aspect of a cancer cell's life, actually have multiple functions."

Molecular Cell 2005;20:539-550.

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