Cell death mystery yields new suspect for cancer drug development

A mysterious form of cell death, coded in proteins and enzymes, led to a discovery by UNC researchers uncovering a prime suspect for new cancer drug development.

CIB1 is a protein discovered in the lab of Leslie Parise, PhD , professor and chair of the department of biochemistry at the University of North Carolina at Chapel Hill. The small calcium binding protein is found in all kinds of cells.

Cassandra Moran, DO, was a pediatric oncology fellow at UNC prior to accepting a faculty position at Duke University. She is interested in neuroblastoma, a deadly form of childhood . While working in the Parise lab at UNC as a resident, she found that decreasing CIB1 in caused cell death.

Cancer is a disease of , so the ability to cause cancer cell death in the lab is exciting to researchers – but the UNC team couldn't figure out how it was happening.

Tina Leisner, PhD, a UNC research associate in biochemistry, picked up where Dr. Moran left off when she returned to her clinical training.

"It was a mystery how loss of CIB1 was causing cell death. We knew that it wasn't the most common mechanism for programmed cell death, called apoptosis, which occurs when enzymes called caspases become activated, leading to the destruction of . These cells were not activating caspases, yet they were dying. It was fascinating, but frustrating at the same time," said Leisner.

What Dr. Leisner and her colleagues found, in the end, is that CIB1 is a master regulator of two pathways that use to avoid normal mechanisms for . These two pathways, researchers believe, create "alternate routes" for and proliferation that may help cancer cells outsmart drug therapy. When one pathway is blocked, the other still sends signals downstream to cause cancer cell survival.

"What we eventually discovered is that CIB1 sits on top of two cell survival pathways, called PI3K/AKT and MEK/ERK. When we knock out CIB1, both pathways grind to a halt. Cells lose AKT signaling, causing another enzyme called GAPDH to accumulate in the cell's nucleus.Cells also lose ERK signaling, which together with GAPDH accumulation in the nucleus cause neuroblastoma cell death. In the language of people who aren't biochemists, knocking out CIB1 cuts off the escape routes for the cell signals that cause uncontrolled growth, making CIB1 a very promising drug target," said Dr. Parise.

This multi-pathway action is key to developing more effective drugs. Despite the approval of several targeted therapies in recent years, many cancers eventually become resistant to therapy.

"What is even more exciting," Leisner adds, "is that it works in completely different types of cancer cells. We successfully replicated the neuroblastoma findings in triple-negative breast cancer cells, meaning that new drugs targeted to CIB1 might work very broadly."

More information: The team's findings were published in the journal Oncogene.

add to favorites email to friend print save as pdf

Related Stories

Research identifies how cancer cells cheat death

Jun 08, 2011

Research led by David Litchfield of The University of Western Ontario has identified how biochemical pathways can be "rewired" in cancer cells to allow these cells to ignore signals that should normally trigger their death. ...

An Achilles heel in cancer cells

Dec 08, 2008

A protein that shields tumor cells from cell death and exerts resistance to chemotherapy has an Achilles heel, a vulnerability that can be exploited to target and kill the very tumor cells it usually protects, researchers ...

Recommended for you

Unraveling the 'black ribbon' around lung cancer

Apr 17, 2014

It's not uncommon these days to find a colored ribbon representing a disease. A pink ribbon is well known to signify breast cancer. But what color ribbon does one think of with lung cancer?

User comments