Cancer researchers have found that the tumor suppressing protein FOXO3a (a Forkhead transcription factor) behaves like a tumor enhancer in human anaplastic thyroid cancer (ATC) cells.

ATC is a serious health threat, since while it accounts for just 2% percent of thyroid cancer cases in the US it is responsible for about 40% of thyroid cancer deaths.

Investigators at the Mayo Clinic (Jacksonville, FL, USA) evaluated the effect of an Akt (protein kinase B) blocker - similar to the ones now being tested in human cancer clinical trials – on cultures of ATC cells.

The data they obtained was both unexpected and worrying. They reported in the June 20, 2012, online edition of the Journal of Cell Science that blocking Akt – which was supposed to inhibit cancer cell growth – stimulated the growth of ATC cells.

In most types of cancers, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Removed from the nucleus FOXO3a cannot block cell growth. However, in ATC cells FoxO3a remains nuclear. This nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. On the other hand, silencing FoxO3a with a reverse genetics approach led to down-regulation of CCNA1 (cyclin A1) mRNA and protein.

“This result is exactly the opposite of what we expected,” said senior author Dr. John A. Copland, professor of cancer biology at the May Clinic. “We were more than surprised. We were concerned. Cancer researchers, including those testing Akt inhibitors, should know that FOXO3a has pro-cancer activity as well as anticancer properties. Concern should be raised that an Akt inhibitor will enhance retention of FOXO3a in the nucleus, causing FOXO3a to remain active.

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