Molecular switch that allows melanoma to resist therapy

By Heather Buschman, Ph.D.
February 2, 2012
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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. 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 Cɛ (PKCɛ), 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 PKCɛ in melanoma are associated with poor prognosis.

“PKCɛ is the culprit behind melanoma’s ‘oncogenic addiction,’” said Ronai, associate director of Sanford-Burnham’s NCI-designated Cancer Center and senior author of the study. “ATF2 is normally a ‘good guy.’ But when there is too much PKCɛ—as in malignant melanoma—ATF2 becomes an oncogene, promoting tumor development.”

In this study, Ronai and lead author Eric Lau, Ph.D., a postdoctoral researcher in his lab, found that PKCɛ’s malignant power is in its ability to direct ATF2’s location and activity within a cell. In a normal cell, PKCɛ 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), PKCɛ 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.

PKCɛ levels are abnormally high in melanoma, and more PKCɛ 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 PKCɛ 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 PKCɛ’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 PKCɛ 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.”

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Original paper:
Lau E, Kluger H, Varsano T, Lee K, Scheffler I, Rimm DL, Ideker T, & Ronai ZA (2012). PKCε Promotes Oncogenic Functions of ATF2 in the Nucleus while Blocking Its Apoptotic Function at Mitochondria. Cell, 148 (3), 543-55 PMID: 22304920

Click here to read more blog posts about Ze’ev Ronai, Ph.D. and his research

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Heather Buschman, Ph.D.

Heather was an SBP Communications staff member.

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2 Comments

  1. Pingback: Sanford-Burnham study finds molecular switch that allows melanoma to resist therapy – Cancer Facts

  2. Melanoma is a cancer that sttars in a certain type of skin cell.Here is what a melanoma appears like:asymmetry – the condition of a single half does not match up the other.Border – the edges are typically ragged, notched, blurred, or irregular in outline; the pigment may perhaps distribute to the surrounding skin.Color – the coloring is uneven. Shades of black, brown, and tan may perhaps be present. locations of white, grey, red, pink, or blue also may perhaps be seen.Diameter—there may be a alter in size, generally an increase. Melanomas are generally bigger compared to eraser of the pencil (1/4 inch or five millimeters).Watch for modifications in the molemelanomas in an earlier point may perhaps be discovered when an current mole modifications slightly, for example, when a brand name new dark region forms. Newly shaped good scales and itching in the mole also are typical signs and symptoms of earlier melanoma. In much more innovative melanoma, the texture within the mole may perhaps change. For example, it may perhaps turn into tough or lumpy. Melanomas may perhaps really feel unique from standard moles. much more innovative tumors may perhaps itch, ooze, or bleed. But melanomas generally do not bring about pain.Hope this has helped!

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