Some of Our Cells Are Defying Death. Scientists Just Discovered How.

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Here’s what you’ll learn when you read this story:

• When cells are about to die, they send signals that trigger proteins which are supposed to destroy them, but it doesn’t always happen that way.

• Some cells activate the signal but then resist the executioner proteins even in the face of punishing conditions like extreme radiation.

• Because these cells are a mechanism behind the resistance of certain cancers to radiation, knowing how they function could help develop more effective treatments in the future.

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When most cells die, they quietly succumb to their mortality. Others turn into zombies.

Enzymes known as caspases are the grim reapers that come for cells on their proverbial last breath. Often called executioners, these proteases, enzymes which break apart peptide bonds through hydrolysis, are catalysts that begin the process of apoptosis, or programmed cell death. This is how they dismember the proteins of a dying cell. These proteins are then reused to support the functions of living cells. Caspases are triggered through specific cell death pathways and take cells that are too far gone—whether from pathogens or molecular damage—to the hereafter.

What almost pushes caspases into sci-fi-horror territory is that they can actually cause cells on the brink of death to zombify. A cell on the decline initially signals an initiator caspase so it can set off its own self-destruction, and the initiator activates effector caspases to tear its proteins apart. It isn’t always so straightforward. Something that has left scientists wondering for the past fifty years is why caspases cause some cells on the verge of apoptosis to regenerate damaged tissue and even boost resilience. These cells begin to enter self-destruct mode, but in an unlikely turn, they end up undead.

At his lab in the Molecular Genetics Department of the Weizmann Institute of Science in Israel, molecular geneticists Eli Arama, Tslil Braun and their team of researchers have finally found out how cells that are programmed for death can survive. The team had previously experimented with fruit fly larvae by blasting them with ionizing radiation that should have been lethal on a cellular level. With upgraded technologies that would give them deeper insight, they recently repeated this experiment using a sensor that identified zombie cells. This is how they found why cells in the epithelial, or outer, level of tissue did not all perish.

“We identif[ied] two apoptosis-resistant epithelial cell populations that mediate regeneration after ionizing radiation, Dronc-activating (DARE) and non-activating (NARE) cells,” Arama and Braun said in a study recently published in Nature Communications. “Dronc activity in DARE cells, independent of Dark and effector caspases, drives regeneration both cell-autonomously and non-cell-autonomously.”

Among the seven caspases encoded by the fruit fly (Drosophila melanogaster) genome are the initiator Dronc and effectors Drice and Dcp-1, which are activated by the Dark protein to take apart cells after Dronc has been signaled. Living cells inhibit caspases, but when they are ready to die, this is reversed by the appropriately named Reaper family of proteins that bind to the inhibitor and initiate apoptosis. There were cells that not only dodged the effects of irradiation but repaired damaged tissue and multiplied enough to replenish nearly half of tissue that couldn’t be salvaged. This is the phenomenon of compensatory proliferation.

The cells behind this Frankenstein-esque resurrection were DARE (Dronc-activating radiation-induced apoptosis-resistant epithelial) and NARE (Non-Dronc-activating radiation-induced apoptosis-resistant epithelial) cells. Despite the signal for the initiator caspase being switched on in these cells, even a bombardment of radiation could not destroy them. Arama thinks this was possible because of a protein that prevented the initiator caspase from activating the executioners by attaching it to the cell membrane. DARE cells died and tissue could not regenerate as easily when this protein was turned off.

DARE and NARE cells need each other to function efficiently. DARE cells secrete growth signals that give NARE cells an advantage, while signals from NARE cells contribute to homeostasis by keeping DARE cells from multiplying unchecked. DARE cells also prevent overproliferation of NARE cells. Prevention of cell death can actually be detrimental when it occurs in cancerous tumors, giving them the power to resist radiation treatment. Demystifying how DARE and NARE cells work is a breakthrough that could potentially be used to develop treatments for resistant cancers that would otherwise keep spreading.

“Given that most current anticancer therapies…induce apoptotic cell death, and that approximately two-thirds of cancer patients receive radiotherapy, understanding how certain cells resist radiation-induced apoptosis and subsequently proliferate is critical,” the researchers said. ”Such insights could improve our understanding of cancer recurrence following treatment and guide the development of more targeted and effective therapeutic strategies.”

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