Signalling: Making more of a mark
Nature Reviews Cancer 8, 12 (01 December 2008) | doi:10.1038/nrc2551
Melanomas are resistant to many standard therapies and often metastasize, prompting an intensive search for novel therapeutic targets. A recent study has highlighted a role for Notch signalling in melanoma development under hypoxic conditions.
The Notch signalling pathway controls a range of different cellular processes and aberrant Notch signalling is involved in many cancers. Barbara Bedogni and colleagues found that notch 1 signalling is increased in melanomas compared with normal skin and benign nevi, and observed notch 1 activity in melanomas that lacked expression of the tumour suppressor PTEN and so had constitutively active Akt. The relationship between notch 1 and Akt seems to be complex: notch 1 can induce Akt signalling and is also downstream of Akt signalling. Further analyses showed that Akt can increase notch 1 expression through nuclear factor B, which is a target of Akt in melanoma cells.
The authors have previously shown that Akt-dependent transformation of melanocytes requires hypoxia and they found that notch 1 expression and activity are increased under these conditions. This effect is dependent on the presence of the transcription factor hypoxia-inducible factor 1 (HIF1), and can be inhibited by the expression of a short hairpin RNA (shRNA) that targets HIF1. Moreover, by inhibiting notch 1 using targeted drugs or shRNAs, the authors showed that notch 1 is required for Akt-dependent melanocyte transformation and tumour growth in vivo under hypoxic conditions. Importantly, inhibition of notch 1 resulted in inhibition of cell proliferation in vitro and in vivo. Melanoma cells lacking notch 1 were not apoptotic under normal culture conditions, but were more likely to undergo apoptosis in hypoxic conditions. Therefore, notch 1 activity seems to be crucial for melanoma development and might be a potential therapeutic target for the treatment of this aggressive disease.
ORIGINAL RESEARCH PAPER
- Bedogni, B. et al. Notch 1 is an effector of Akt and hypoxia in melanoma development. J. Clin. Invest. 16 Oct 2008 (doi: 10.1172/JCI36157) | Article |
- Denko, N. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008) | Article |