Abstract
An increased expression and cytoplasmic abundance of the ubiquitous RNA binding protein human antigen R (HuR) is critically implicated in the dysregulated control of post-transcriptional gene expression during colorectal cancer development and is frequently associated with a high grade of malignancy and therapy resistance. Regardless of the fact that HuR elicits a broad cell survival program by increasing the stability of mRNAs coding for prominent anti-apoptotic factors, recent data suggest that HuR is critically involved in the regulation of translation, particularly, in the internal ribosome entry site (IRES) controlled translation of cell death regulatory proteins. Accordingly, data from human colon carcinoma cells revealed that HuR maintains constitutively reduced protein and activity levels of caspase-2 through negative interference with IRES-mediated translation. This review covers recent advances in the understanding of mechanisms underlying HuR’s modulatory activity on IRES-triggered translation. With respect to the unique regulatory features of caspase-2 and its multiple roles (e.g., in DNA-damage-induced apoptosis, cell cycle regulation and maintenance of genomic stability), the pathophysiological consequences of negative caspase-2 regulation by HuR and its impact on therapy resistance of colorectal cancers will be discussed in detail. The negative HuR-caspase-2 axis may offer a novel target for tumor sensitizing therapies.
Highlights
Colorectal cancer (CRC) is one of the most common cancers in the western world
human antigen R (HuR) can impair the translation of pro-apoptotic factors like p27 [54], c-Myc [55], and the type 1 insulin growth factor-receptor (IGF-IR) [56]. In accordance with these reports, we previously identified the pro-apoptotic caspase-2L as a novel target gene, in colon carcinoma cells, which is negatively regulated by HuR, mainly through an inhibition of translation [57]
Activation of caspase-2 via cleavage of the BH3 interacting domain death agonist (Bid) which leads to an increase in truncated Bid can promote apoptosis upstream of the mitochondrial outer membrane permeabilization (MOMP), caspase-3 and caspase-9, and independently of p53 [154] (Figure 2B)
Summary
Colorectal cancer (CRC) is one of the most common cancers in the western world. Despite having a slow progression, it is characterized by the high tumor mortality that is mainly caused by the strong metastatic potential of the primary tumor [1,2]. Prominent examples include the mitogen activated protein kinase (MAPK), Wnt/β-catenin, Notch, p53, phosphoinositide-3-(PI3) kinase, and transforming growth factor (TGF) β signaling pathways (for a review see [5,8]) Alterations in these signaling cascades play a pivotal role in the process of colonic epithelial transformation and in metastasis of CRC. An increasing body of evidence has revealed that besides genetic and epigenetic events, changes in the post-transcriptome encompassing mechanisms that can affect different phases of RNA maturation, including trafficking, degradation and translation, critically contribute to CRC development (for a review see [9,10]) These mechanisms allow for a rapid adaptation to external stress conditions which frequently lead to a global repression of transcription. The role of different RNA binding proteins for gastrointestinal epithelial homeostasis is comprehensively reviewed in previous publications by our colleagues [10,11]
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