What happens when liver cancer drugs delete Akt proteins selectively instead of simultaneously? A recent study funded by the National Institutes of Health and conducted by scientists at the University of Chicago is providing new answers to that question.

Akt proteins come in three variations or isoformes, known as Akt1, Akt2 and Akt3. These proteins are a set of molecules that inform the growth, division and immortality of cancer cells.

While current liver cancer treatment drugs aim to delete all three Akt proteins simultaneously, Dr. Nissim Hay and his team set out to investigate what would happen if the proteins were systemically deleted individually or in different combinations, and what this might mean for drug therapy.
“We knew that the deletion of Akt1 in mice does not have adverse physiological consequences, while the deletion of Akt2 causes hyperinsulinemia. The high level of insulin in the blood of Akt2 null mice could hyperactivate the other Akt isoformes as well as other pro-tumorigenic signaling pathways,” Hay told HCB News.

The researchers found that when both Akt1 and Akt3 were deleted, the mice survived, while deletion of both Akt1 and Akt2 simultaneously caused the mice to die. When Akt1 was systematically deleted in mice with tumors, tumors shrank and mice survived but deletion of Akt2 caused mice to develop high levels of insulin in the blood.

Further experimentation showed that when Akt1 and Akt 2 were deleted from just liver cells in the mice, they developed liver cancer. Moreover, the patterns of gene expression looked similar to those in aggressive human liver cancer.

Hay explained, “there are other studies at the cellular level suggesting that the individual Akt isoforms, despite high homology, have different functions. For instance Akt2 is expressed at the highest level in insulin responsive tissues such as liver and skeletal muscles and consistently Akt2-deficient mice have a diabetic phenotype.”

Likewise, cellular death caused by Akt1 and Akt2 deletion created inflammation from macrophages, a type of immune cell that secretes cytokines, and cytokines contribute to liver cancer. “We provided a genetic proof of concept and based on these studies we could say that in patients with liver inflammation pan-Akt inhibitors could potentially increase the risk of liver cancer,” said Hay.

Hay indicated that his findings are relevant for future cancer treatment protocols. “Liver damage should be examined as well as insulin level in the blood. Efforts should be made to develop specific inhibitors for the individual Akt proteins.”

He said there are still questions to be answered in follow-up studies: why did the mice lose weight, develop hypoglycemia, and die after systemic deletion of both Akt1 and Akt2? He believes this may be due to intestinal damage.

According to Hay, further research should be done to determine how the liver cancer cells could survive and proliferate in the absence of Akt activity. He says, “Understanding this could help us to identify mechanisms of resistance to Akt inhibitors.”

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