February 3, 2012
Sanford-Burnham Researchers Find Molecular Switch That Allows Melanoma To Resist Therapy
Study identifies protein kinase C-epsilon as a molecular switch that determines tumor-promoting or -suppressing activity in skin cells
The National Cancer Institute (NCI) estimates that as many as one in 51 men and women will be diagnosed with melanoma–the deadliest form of skin cancer–at some point during their lifetimes. A research team led by Ze'ev Ronai, Ph.D. at Sanford-Burnham Medical Research Institute (Sanford-Burnham) is working to unravel the molecular mechanisms underlying the development and progression of this disease in hopes of improving prevention and treatment strategies. To do this, Ronai's laboratory has been studying a protein named Activating Transcription Factor 2 (ATF2), which is associated with poor prognosis in melanoma. ATF2 is a two-faced protein–in melanoma cells, it's oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it acts as a tumor suppressor. In a paper published February 3 in the journal Cell, the team identified a molecular switch that controls ATF2's dual functions. This switch is controlled by protein kinase CÎµ (PKCÎµ), which disables ATF2's tumor-suppressing activities, sensitizing cells to chemotherapy; instead, ATF2's tumor-promoting activity is enhanced. The team also found that high levels of PKCÎµ in melanoma are associated with poor prognosis.
In this study, Ronai and lead author Eric Lau, Ph.D., a postdoctoral researcher in his lab, found that PKCÎµ's malignant power is in its ability to direct ATF2's location and activity within a cell. In a normal cell, PKCÎµ modifies ATF2, keeping it in the nucleus, where it turns genes on and off and helps repair damaged DNA. When the cell experiences exposure to toxicity or stress (radiation, for example), PKCÎµ backs off and ATF2 is able to move out of the nucleus and to the mitochondria, the part of the cell that generates energy and helps control cellular life and death. When it gets there, ATF2 helps to set the cell on a death course–a safeguard cells use to prevent errors that often make them cancerous.
PKCÎµ levels are abnormally high in melanoma, and more PKCÎµ means more ATF2 stuck in the nucleus, where it can't help the cells to die. Instead, in the nucleus, ATF2 promotes cellular survival and thus contributes to tumor development.
"We found that melanoma patients with high PKCÎµ levels in their primary tumors were more likely to experience shorter survival times," said Lau. "This finding is consistent with earlier analyses of human melanoma tumors that showed a similar correlation between increased nuclear ATF2 and poor clinical outcome."
The Ronai laboratory, in collaboration with Sanford-Burnham's Conrad Prebys Center for Chemical Genomics, is currently searching for small molecules that help release ATF2 from PKCÎµ's grip, thereby resuming ATF2's ability to promote cell death when needed. Since such an approach will effectively kill melanoma cells, it is expected to offer new therapeutic options for melanoma, and possibly other tumors with high PKCÎµ levels.
"This work has clear potential for translation from a basic laboratory discovery to a melanoma therapy," said Michael Jackson, Ph.D., vice president of drug discovery and development at Sanford-Burnham. "We are excited to begin the screening process to identify a new class of drugs to treat cancer."
This study was funded by the National Cancer Institute (grants CA099961, CA051995, and CA121949) and the American Cancer Society, Illinois Division (fellowship PF-09-112-01-GMC). The study's co-authors include Eric Lau, Sanford-Burnham; Harriet Luger, Yale University; Tal Varsano, Sanford-Burnham; KiYoung Lee, University of California, San Diego and Ajou University; Immo Scheffler, University of California, San Diego; David Rimm, Yale University; Trey Ideker, University of California, San Diego; and Ze'ev A. Ronai, Sanford-Burnham.
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