Evidence for the Possible Biological Significance of the igf-1 Gene Alternative Splicing in Prostate Cancer

Abstract

Insulin-like growth factor-I (IGF-I) has been implicated in the pathogenesis of prostate cancer (PCa), since it plays a key role in cell proliferation, differentiation, and apoptosis. The IGF-I actions are mediated mainly via its binding to the type I IGF receptor (IGF-IR), however IGF-I signaling via insulin receptor (IR) and hybrid IGF-I/IR is also evident. Different IGF-I mRNA splice variants, namely IGF-IEa, IGF-IEb, and IGF-IEc, are expressed in human cells and tissues. These transcripts encode several IGF-I precursor proteins which contain the same bioactive product (mature IGF-I), however, they differ by the length of their signal peptides on the amino-terminal end and the structure of the extension peptides (E-peptides) on the carboxy-terminal end. There is an increasing interest in the possible different role of the IGF-I transcripts and their respective non-(mature)IGF-I products in the regulation of distinct biological activities. Moreover, there is strong evidence of a differential expression profile of the IGF-I splice variants in normal versus PCa tissues and PCa cells, implying that the expression pattern of the various IGF-I transcripts and their respective protein products may possess different functions in cancer biology. Herein, the evidence that the IGF-IEc transcript regulates PCa growth via Ec peptide specific and IGF-IR/IR-independent signaling is discussed.

The human Ec peptide: the active core of a progression growth factor with species-specific mode of action

“…In the first series of experiments, the cells were seeded for 24hrs after plating and the media continued to be supplemented with 10% FBS during the experimental procedure. We then added various doses of the scrambled peptide (negative control), mature IGF-1 peptide (positive control), hEc, mE and the synthetic hEc fragments, hEc (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), hEc (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), hEc, [21][22][23][24] for 48 hrs. In the second type of experiments, after the cell plating, the culture media were changed to contain 0.5% FBS for 48 hrs.…”

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

“…All possible combinations between promoter usage and terminal exon (5 or 6) can occur in different IGF-I transcripts (45,51,52). It has been proposed that the use of promoter 1 could be associated with the synthesis of paracrine IGF-I and may influence interactions with insulinlike growth factor binding proteins (IGFBPs), or promote the formation of the truncated IGF-I peptide (46), (see below: IGF-I Processing, Secretion and Glycosylation).…”

“…The IGF-IR exhibits a high degree of homology to IR (110) and, given the significant structural similarity between IGF-I and insulin, these ligands can cross-activate both receptors, while the IGF-IR signaling pathways share multiple intracellular mediators with the insulin signaling cascade (19,52). The IGF-IR/IR hybrid receptor is thought to function predominantly as an IGF-I receptor, since its binding affinity for insulin is lower than that for IGF-I, however the functional importance of IGF-IR/IR hybrid receptor remains poorly understood (74,109,111).…”

“…Biological actions of IGF-I are modulated by a family of at least six IGFBPs (52,75,, which interact mainly with the residues 1-3 and 49-51 of mature IGF-I (113), (see Figure 1A). In general, IGFBPs transport IGF-I and increase its half-life in the circulation; most of the circulating IGF-I is protected from proteolytic degradation by forming a ternary complex with IGFBP-3 and the glycoprotein acid-labile subunit (ALS) (74,122).…”

“…The diversity and the patterns of differential expression have been proposed to reflect potential biological activities associated with the E domain peptides (27,52). Divergent actions and signaling of the different pro-IGF-I forms or mature IGF-I lacking any E-peptide have been reported after viral-mediated expression of the IGF-I isoforms (IGF-IA and IGF-IB) in mouse skeletal muscle (36,132).…”