Inhibition of the Notch Signaling Pathway Blocks Lung Cancer Growth in Mouse Model

Spanish researchers have shown that gamma-secretase inhibitors, which block the Notch signaling pathway, effectively stopped the growth of human lung cancer (non-small-cell lung carcinomas or NSCLCs) in a mouse model of the disease.

The notch-signaling pathway is important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. The NOTCH gene has been identified as an important oncogene for the development of leukemias, pancreatic, and lung cancer.

In a recent study, investigators at the National Cancer Research Center (Madrid, Spain) worked with a genetically modified mouse model that faithfully recapitulated human lung cancer. They blocked Notch signaling in these animals by treating them with a gamma-secretase inhibitor (GSI).

Results published in the August 14, 2012, issue of the journal Cancer Cell revealed that GSI treatment blocked NSCLC growth in the mice. At the molecular level it was found that treated carcinomas presented reduced levels of transcription factor HES1 (hairy and enchancer of split-1) and reduced phosphorylated ERK (extracellular-signal-regulated kinase) without changes in phosphorylated MEK (mitogen-activated protein kinase). HES1 directly bound to and repressed the promoter of DUSP1 (dual specificity phosphatase 1), encoding a dual phosphatase that was active against phospho-ERK. Accordingly, GSI treatment was seen to upregulate DUSP1 and decrease phospho-ERK.

"Notch regulates cell proliferation in lung cancer," said senior author Dr. Manuel Serrano, head of the tumor suppression group at the [Spanish] National Cancer Research Center. "We have found that this protein cooperates with the Ras oncogene, a key element in the formation of these tumors."

Related Links:
National Cancer Research Center