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HtrA serine proteases as potential therapeutic targets in cancer - PubMed

Review

HtrA serine proteases as potential therapeutic targets in cancer

Jeremy Chien et al. Curr Cancer Drug Targets. 2009 Jun.

Abstract

The human HtrA family of serine proteases consists of four members: HtrA1, HtrA2, HtrA3 and HtrA4. Although prokaryotic HtrA proteins are well characterized in their dual roles as chaperones and proteases that degrade misfolded proteins in the periplasm, some members of mammalian HtrA proteins are described as potential modulators of programmed cell death and chemotherapy-induced cytotoxicity. Goal of this review article is to describe the molecular alterations associated with these HtrA serine proteases and how these alterations may be associated with tumor behavior and response to chemotherapy. We will also discuss evidence that chemotherapeutic drugs regulate the expression and activation of HtrA serine proteases and that these proteases contributes to programmed cell death. Finally, we will discuss the potential role of epigenetic therapy in targeting the expression and activation of HtrA serine proteases and the mechanisms by which these proteases enhance cytotoxic effect of conventional chemotherapy.

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Figures

Figure 1
Figure 1

Genomic sequence analysis of the promoter and exon 1 of HTRA genes for the presence of putative CpG islands. Each analysis contains 1000 bases of promoter and entire exon 1. Emboss CpGPlot web-based program with default settings was used to identify putative CpG islands in HTRA genes. Schematic representation of CpG sites, indicated by vertical lines, was obtained from CpG Island Searcher web program.

Figure 2
Figure 2

DNA sequence analyses of bisulfite-modified genomic DNA corresponding to a putative CpG island in HTRA1 promoter. A) CpG sites are methylated in HtrA1-deficient A2780, but not methylated in HtrA1-expressing SKOV3 cells. Methylated CpG sites (underlined in A2780 sample) were resistant to bisulfite conversion and remained as Cs whereas unmethylated CpG sites (underlined in SKOV3 sample) were converted to Ts. In addition, two sinle nucleotide polymorphisms were indicated by arrowheads. B) HtrA1 expression is re-activated wit 5-aza-2’-deoxycytidine (DAC) or LBH589 treatments in two non-expressing cell lines.

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