Sept 13, 2013 鈥� Discovery by 黑料网 researchers in the Parise lab uncover a prime suspect for new cancer drug development. The team鈥檚 findings were published in the journal Oncogene.
CIB1 is a protein discovered in the lab of , professor and chair of the at the . The small calcium binding protein is found in all kinds of cells.
Cassandra Moran, DO, was a pediatric oncology fellow at 黑料网 prior to accepting a faculty position at Duke University. She is interested in neuroblastoma, a deadly form of childhood brain cancer. While working in the Parise lab at 黑料网 as a resident, she found that decreasing CIB1 in neuroblastoma cells caused cell death.
Cancer is a disease of uncontrolled cell growth, so the ability to cause cancer cell death in the lab is exciting to researchers 鈥� but the 黑料网 team couldn鈥檛 figure out how it was happening.
Tina Leisner, PhD, a 黑料网 research associate in biochemistry, picked up where Dr. Moran left off when she returned to her clinical training.
鈥淚t was a mystery how loss of CIB1 was causing cell death. We knew that it wasn鈥檛 the most common mechanism for programmed cell death, called apoptosis, which occurs when enzymes called caspases become activated, leading to the destruction of cellular DNA. These cells were not activating caspases, yet they were dying. It was fascinating, but frustrating at the same time,鈥� said Leisner.
What Dr. Leisner and her colleagues found, in the end, is that CIB1 is a master regulator of two pathways that cancer cells use to avoid normal mechanisms for programmed cell death. These two pathways, researchers believe, create 鈥渁lternate routes鈥� for cell survival 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.
鈥淲hat 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鈥檚 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鈥檛 biochemists, knocking out CIB1 cuts off the escape routes for the cell signals that cause uncontrolled growth, making CIB1 a very promising drug target,鈥� 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.
鈥淲hat is even more exciting,鈥� Leisner adds, 鈥渋s 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.鈥�
The team鈥檚 findings were published in the journal Oncogene. In addition to Drs. Leisner, Moran and Parise, Stephen P. Holly, PhD, contributed to the research.
Research reported in this publication was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health under awards number HL07149T32 and 5R01HL092544.
Media contact: Ellen de Graffenreid, 919-962-3405, ellen_degraffenreid@med.unc.edu
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