05:46am Saturday 25 January 2020

Stephen D. Nimer, M.D., Pinpoints New Way to Kill Cancer Cells in Science Signaling Study

In the study, Nimer and his team demonstrate for the first time that Akt, a member of the family of kinase proteins that fine tunes the activity of other proteins, inhibits the function of Bmi1, a protein critical to the renewal of stem cells that are implicated in cancer. Their study showed that Akt and Bmi1 interact, a finding that not only provides insight into a novel biological pathway, but opens the door to better treatments for leukemia and possibly other cancers.

“Stem cells never exhaust. They keep renewing as long as they stay stem cells,” explained Nimer, the study’s senior author. “But we found that Bmi1, a protein previously known to be important for the renewal properties of stem cells, loses its function when it is phosphorylated by Akt. And when Bmi1 loses its function, the stem cells lose their ability to remain stem cells. So, in essence, this discovery gives us a chance to learn how to kill cancer cells by activating Akt.”

Added the study’s lead author, Yan Liu, Ph.D., now assistant professor of pediatrics at Indiana University School of Medicine, “This changes a common belief. Most of us believed when you have activation of Akt, it is a bad thing. But that may not always be the case. There is what we call ‘context-dependency,’ meaning it depends on the situation. It is not absolute.”

Titled “Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor Suppressing Ink4a-Arf locus,” the Science Signaling study builds on research that Nimer and Liu began at Memorial Sloan-Kettering Cancer Center to pinpoint the differences in how normal stem cells and cancer stem cells renew, all with the goal of developing therapeutics that kill cancer stem cells but leave normal ones alone.

From that work, they noticed that cells with activation of Akt seemed to behave similarly to cells that lost Bmi1 function. So, they set out to investigate whether the two proteins have a functional interaction. They were surprised to learn they do, but happy to conclude that this interaction could be exploited to improve a new class of kinase-inhibiting drugs.

As the study authors wrote, “This suggests that the inhibitory effects of Akt on Bmi1 function could have therapeutic implications. Phosphorylation (and inactivation) of Bmi1 by Akt could limit hematopoietic stem cell self-renewal, and superactivation of Akt signaling could potentially extinguish the cancer stem cell pool.”

In addition to Nimer, Liu and others from Sloan-Kettering, researchers from Harvard Medical School contributed to the study.

University of Miami

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