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GEN News Highlights : Apr 11, 2014

Novel Molecular Target for Asthma and Cancer Identified

Researchers at the Johns Hopkins Kimmel Cancer Center described an enzyme involved in T-cell regulation that could be a useful target in treating asthma and boosting the effects of certain cancer therapies.

In a study (“The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex”) published in Nature Immunology, the scientists demonstrated that mice without the enzyme SGK1 were resistant to dust mite-induced asthma. And mice with melanoma and missing the enzyme developed far fewer lung tumors (less than half as many) than mice with SGK1.

“If we can develop a drug that blocks the enzyme in a way that mimics what happens when the enzyme is missing, we would not only have a treatment to inhibit asthma, but also a drug that could be used in conjunction with other experimental therapies aimed at helping the immune system fight cancer,” said Jonathan D. Powell, M.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center.

The unusual dual potential of an SGK1-blocking compound stems from the enzyme's role in a key pathway linked to T cells, which act as either “generals” of the immune system by directing how the system works, or “soldiers” that seek and destroy foreign cells, according to Dr. Powell. He and his colleagues decided to look at SGK1 because it works along the same pathway of a protein called mTOR, a focus of their previous research. The mTOR pathway helps T cells decipher signals from their environment, and prompts the cells to transform into specific T-cell types.

As part of this pathway, SGK1 dials down production of interferon-gamma, a signaling protein. When SGK1 is inactive, T cells produce increased amounts of interferon-gamma that appear to be useful in fighting tumor cells.

“We found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2,” wrote the investigators. “Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection, and more readily rejected tumors.”

Dr. Powell said that by untangling the different effects of SGK1, his team has advanced efforts to fine-tune immune responses in patients. “We're not suppressing or exacerbating the immune system, we're regulating it,” he noted. “We're regulating it to do exactly what we want it to do.”