Targeting a protein in order to fight against intestinal cancer
A total inhibition of the Wnt signalling pathway is not appropriate, given its key role in homeostasis. “Ideally, a more targeted effect on proteins only involved in the constitutive activation of Wnt signaling is required. We think we have identified this protein: it is ELP3”. For several years now, Pierre Close, a research associate at the FRS-FNRS and head of the Laboratory of Cancer Signalling (GIGA-Research, “Molecular Biology of Diseases” Unit), who published this study with Alain Chariot, has been working on Elongator, a six subunits complex (ELP1-6). He has been working more specifically on ELP3, which is involved in other areas (Read : Neuron migration ‘under the wing’ of Elongator). Both collaborators have therefore sought to understand its involvement in the development of intestinal cancer cells. APC and ELP3When APC is lost, β-catenin stabilises and cells proliferate in an uncontrolled manner. “ Mice lacking APC spontaneously develop tumours due to constitutive Wnt signaling. When the Wnt pathway was constitutively activated, ELP3 expression increased which led us to envision that its inactivation may impact on Wnt-driven tumour initiation. We then looked at mice in which we had inactivated the gene encoding ELP3 in intestinal stem cells. In healthy mice, the architecture of intestinal crypts was unchanged. The stem cells remained functional and we only detected a lower number of Tuft cells upon ELP3 deficiency. But as their exact role is still unclear, it is difficult to know what the implications of such defect. We can, however, conclude from this observation that ELP3 is involved in the production of Tuft cells…” A potential targetThe tumour has to synthesise several proteins, such as SOX9, for example, to develop and grow: the essential role of ELP3 can be explained by the fact that many proteins, including SOX9, require ELP3 in order to be synthesised. “We are trying to find a specific pharmacological inhibitor for ELP3 to see whether its inhibition leads to tumour regression in circumstances in which Wnt signaling is constitutively activated. ELP3 is an interesting target because it is a Wnt effector and is involved in the development of cancer cells while being dispensable to intestinal homeostasis…” |
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© 2007 ULi�ge
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