Research led by Daitoku Sakamuro, PhD, Assistant Professor of Pathology at LSU Health Sciences Center New Orleans and the LSUHSC Stanley S. Scott Cancer Center, has identified a protein that enables the activation of a DNA-repair enzyme that protects cancer cells from catastrophic damage caused by chemo and radiation therapy.
This protein, called c-MYC oncoprotein, can initiate and promote almost all human cancers and discovering the role it plays in cancer treatment resistance may lead to advances that save lives. The work is published in the March 29, 2011 issue of Science Signaling, a publication of the American Association for the Advancement of Science. Although scientists have known that cancer cells can acquire resistance to DNA-damaging therapeutic agents, the genetic mechanisms through which this occurs have remained unclear until now.
Using the chemotherapy drug, cisplatin (which is commonly used as a first-line therapy for various cancers) to design a set of experiments, the research team found that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of a c-MYC inhibitor called BIN1. BIN1 suppressed an enzyme essential for DNA repair, and the sensitivity of cancer cells to cisplatin depended upon BIN1 abundance. Overproducing the c-MYC oncoprotein repressed BIN1, blocking its life-saving action.
"Our study provides a potent and novel mechanism through which cancer acquires resistance to DNA damage," notes Dr. Sakamuro. "Inhibition of oncogenic c-MYC may provide an attractive strategy for cancer therapy in combination with DNA-damaging agents."
The researchers also propose that analyzing the levels of the c-MYC and BIN1 proteins or their mutational status may also serve as a valuable prognostic marker to determine whether a cancer will respond to an aggressive dose of therapeutic agents.
According to the American Cancer Society, about 1,529,560 new cancer cases were expected to be diagnosed in the United States in 2010, excluding noninvasive cancers as well as basal and squamous cell skin cancers. Cancer accounts for nearly one quarter of the deaths in the US with an estimated 569,490 cancer deaths expected last year.
"Our study will determine how we can re-sensitize malignant cancer cells to conventional DNA-damaging therapeutic agents and how we can minimize unnecessary side effects associated with cytotoxic chemo and radiation therapy," adds Dr. Sakamuro.
In addition to LSU Health Sciences Center New Orleans, the research team included scientists from Purdue University, West Lafayette, Indiana.
The research was supported by grants from the US Army Department of Defense, National Institutes of Health, Louisiana Cancer Research Consortium, Susan G. Komen Foundation, Walther Cancer Foundation, and Wendy Will Case Cancer Fund.
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