en diversos ámbitos del derecho
2. Las medidas cautelares. Tipos y finalidades en diversos ámbitos del derecho
The phenomena observed upon APP depletion were reversed by overex- pression of AICD. Unbound AICD is unstable and the factor Fe65 is thought to stabilize it (Kimberly et al., 2001). Nonetheless, Fe65 is only one of the many binding partners of AICD participating in AICD signaling and functions (Beckett, 2012). The identification of the AICD binding partner mediating all the effects presented here is beyond the scope of this dissertation. This AICD binding part- ner, once identified, could be targeted using a small molecule to disrupt its inter- action with AICD. Using this strategy, we could reproduce the effects of APP ge- netic ablation in hypoxic tumor tissue. Small molecules could be more effective than large inhibitors, like GSI, in reaching hypoxic areas of tumors, which are, by definition, distant from the vasculature.
Cleavage of APP and AICD generation is reminiscent of Notch receptor cleavage and production of the NICD. The therapeutic efficacy of humanized monoclonal antibody mediated inhibition of Notch signaling is still under investi- gation. These antibodies were shown to prevent Notch cleavage and diminish Notch mediated downstream signaling (Falk et al., 2012). Similar antibodies could be utilized to prevent cleavage of APP and AICD dependent signaling. Still, antibodies are large molecules and their delivery to distant, hypoxic tumor tissue could be problematic.
Alternatively, novel signaling molecules downstream from APP and identi- fied in this project, could be used as therapeutic targets, alone or in combination
with APP targeting. One of the most promising candidates is STYX, because it generates a phenotype that can be potentially detrimental to hypoxic NSCLC cells upon its inhibition.
In conclusion, we have demonstrated a novel role for APP in moderating
cell growth during G0/G1 transition. Disruption of APP signaling leads to necrotic
cell death of hypoxic NSCLC cells. These findings have far-reaching implications in our understanding of hypoxic cancer cell biology and provide a novel therapeu- tic target for the treatment of NSCLC.
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