Drug Discovery Opinion

FOXO3a is a member of the O subclass of fork-head transcription factors, so-called because of their distinctive forked DNA binding domain. It is negatively regulated by phosphorylation through the PI3K/Akt pathway, which confines the transcription factor to the cytoplasm. Generally, FOXO3a is considered to be pro-apoptotic and, as such, a tumour suppressor. The PI3K/Akt pathway is up-regulated in many cancers, consistent with reduced transcriptional activity of FOXO3a. Further, FOXO3a has been reported to mediate the cytotoxic activity of chemotherapeutic agents such as cisplatin and paclitaxel.

In contrast, a pro-survival role for FOXO3a in oxygen-deprived cells has also been reported (Molecular Cell 28, 941–953, December 28, 2007). In this study, from scientists at the Campbell Family Institute for Breast Cancer Research, University Health Network, Ontario Cancer Institute and Princess Margaret Hospital, Toronto, FOXO3a inhibited HIF-1 induced apoptosis in both normal and cancer cells under hypoxic conditions.

Now new research from the Mayo Clinic in Florida and Harvard Medical School has shown that FOXO3a promotes invasive migration of tumour cells in response to hypoxia, mediated by induced expression of matrix metalloproteinases (Molecular and Cellular Biology, September 2009, p. 4906-4917, Vol. 29, No. 18). This tumour cell migration ultimately opens the door to metastasis.

Clearly a pro-apoptotic or pro-survival role for FOXO3a is dependent on context. The challenge for drug discovery is to determine if, when and how therapeutic intervention in this pathway is viable.

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