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ISABEL LÓPEZ DE SILANES Y MANEL ESTELLER AN. R. ACAD. NAC. FARM.

mRNA STABILITY AS A TARGET FOR THERAPY

By gaining a more detailed knowledge of the 3’UTR regulatory
sequences and the trans-acting factors specifically binding to them
it will be possible to design effective therapies. As noted earlier, a
6-bp polymorphism in the 3’UTR of thymidylate synthase decreases
mRNA levels (13) and, thereby could be useful in predicting the
efficacy of TYMS-targeted chemotherapy treatment. TNF-a is
effective in the treatment of advanced solid tumors such as
melanoma and soft tissue sarcoma. When analyzing mRNA levels
of 22 genes in tumor biopsies from patients treated with doxorubicin
alone or combined with TNF-a, TIA-1 was the only gene differentially
expressed between the two groups. When TNF-a effects were tested
in vitro in endothelial cells, fibroblasts, CTLs and NK cells, TIA-1
became upregulated only in endothelial and NK cells. These findings
could indicate that TNF-a -induced TIA-1 overexpression might
sensitize endothelial cells to proapoptotic stimuli present in the
tumor microenvironment and enhance NK cell cytotoxic activity
against cancer cells (35). The chemotherapeutic agent Prostaglandin
A2 (PGA2) causes growth arrest associated with decreased cyclin D1
in several cell lines. PGA2 leads to the destabilization of cyclin
D1 mRNA via a 3’UTR element that binds the RNA-binding protein
AUF1 (36). These studies underscore the potential importance of
understanding 3’UTR regulation in cancer therapy.

Alteration on mRNA stability rates might possibly be cured
by pharmacological approach by correcting the stabilization/
degradation mRNA rates. The specific approach, eventually, would
be targeting the correct mRNA since AUBPs bind to a wide variety
of mRNA targets and exogenous compound might affect a broad
array of genes. If there is an increased in mRNA stabilization, in
order to deacrease the RNA levels, the ARE subregion can be targeted
by antisense oligodeoxynucleotides (ODNs) or ribozymes. By
contrast, when the mRNA is destabilized by mutations or altered
binding to RNA degradation-promoting AUBPs, synthetic
oligoribonucleotides (ORNs) are worth considering since they do not
activate catabolic processes like ODNs. The hybridization of ORN to
ARE sequences might insulate/protect ARE from «contact» with
cellular trans-acting factors (AUBPs) and the exosome (machinery

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