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In Greek mythology, one of Hercules’ labors was to slay the Hydra. The task seems impossible, as the creature was a multi-headed monster with the ability to grow two new heads when one was cleaved off. Oncologists face a similar daunting task in eliminating malignant cells, as each cancer appears to have its own Hydra protecting it. The suppression of the Forkhead box class O (FOXO) family of transcription factors is a common event in many cancers, including acute leukemias. FOXO3A can serve as a tumor suppressor, as it positively regulates genes that promote apoptosis (e.g., Bim, FAS ligand) and cell cycle arrest (p21 and p27).^1,2 FOXO3A phosphorylation results in the ubiquitination, nuclear expulsion and proteolysis of the transcription factor.^2-4 Inactivation of FOXO3A is complex, as the mechanism involves a number of different survival kinases, including protein kinase B (AKT), IκB kinase b (IKKβ) and extracellular receptor kinase (ERK). Further complicating matters, each kinase recognizes different sites, so suppression of FOXO3A occurs at multiple levels. Of the FOXO3A kinases, the majority of focus is on AKT. Such attention is logical, as aberrant activation of AKT by mutation of upstream regulators is common in many cancers.⁵ Mutations that induce AKT activation involve inactivation of negative regulators, such phosphatase and Tensin homolog (PTEN), or constitutive activation of positive AKT regulators, such as Phosphoinositide-3 kinase (PI3 Kinase), rat sarcoma (RAS) and Fms-like tyrosine kinase receptor-3 (FLT-3). The FLT-3 internal tandem duplication mutation (FLT-3ITD) is an especially poor prognostic factor for acute myeloid leukemia (AML) patients. Kornblau and colleagues recently demonstrated that phosphorylation of FOXO3A is an adverse prognostic factor for survival and resistance to therapy for AML patients.⁶ Not surprisingly, FOXO3A phosphorylation levels were higher in AML patients with abnormal FLT-3.⁶ However, AKT cannot always account for FOXO3A suppression. Mien-Chi Hung’s group identified IKKβ as a key suppressor of FOXO3A in breast cancer cells lacking active AKT.⁷ Targeting IKK to suppress NFκB signaling became especially appealing as a novel chemotherapy strategy, with the possibility that activation of FOXO3A could occur.³ Strategies to target IKK in T cell acute lymphoblastic leukemia (T-ALL) would seem promising, as IKK/NFκB signaling appear to be especially important in this disease. Activating Notch mutations occur in a majority of T-ALL patients and Notch signaling has been suggested to maintain T-ALL cells by activating NFκB and IKK.⁸ In a recent issue of Cell Cycle, Buontempo and colleagues found that a novel IKKβ inhibitor, BMS-345541, effectively kills T-ALL cells that contain Notch mutations by a mechanism involving FOXO3A activation.⁹ The study demonstrated that the IKK inhibitor potently suppressed IKK/NFκB signaling but did not block AKT or ERK activity. BMS-345541 was effective at inducing FOXO3A activity, as the drug induced nuclear localization of the transcription factor and increased expression of the FOXO3A gene target p21.⁹ It appears, at least in T-ALL cells containing Notch mutations, that IKKβ is responsible for suppressing FOXO3A, as use of the highly specific AKT inhibitor MK-2206 had no impact on FOXO3A nuclear localization or gene expression of its target genes.⁹ Importantly, Buontempo and colleagues found that BMS-345541 was efficient in killing primary T-ALL blast cells derived from pediatric patients. Targeting IKK could prove to be beneficial to these and other patients, especially if their malignant cells contain wild-type p53. FOXO3A and p53 share some common regulatory elements.³ Nuclear export of both molecules involves Exportin-1 (CRM-1). Furthermore, proteosomal degradation of both molecules is mediated by the E3 ubiquitin ligase murine double minute 2 (MDM2).^3,4 Since MDM2 expression is mediated by IKK/NFκB, it is possible that both FOXO3A and p53 could be activated to kill tumor cells. Still, p53 mutations are common in cancer, and it is likely that at least for activation of FOXO3A, an approach to inactivate more than one of its suppressors will be likely. As Hercules was successful in slaying the Hydra with the aid of his nephew Iolaus, it is our hope that inclusion of IKK inhibitors and other agents that can activate FOXO3A as suggested by the Martelli group for T-ALL therapy will result in more effective treatments for T-ALL and other cancers.

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