Do Glycine-Extended Hormone Precursors have Clinical Significance?

Abstract

Half of the known peptide hormones are C-terminally amidated. Subsequent biogenesis studies have shown that the immediate precursor is a glycine-extended peptide. The clinical interest in glycine-extended hormones began in 1994, when it was suggested that glycine-extended gastrin stimulated cancer cell growth. Accompanying findings of gastrin gene expression in common cancers spurred the interest. The interest is now accompanied by skepticism, which is due to failure to demonstrate truly specific receptors for glycine-extended peptides and failure to demonstrate separate physiological and clinical effects of glycine-extended precursors for most other amidated hormones than gastrin and cholecystokinin (CCK). The idea of glycine-extended peptides as independent messengers was interesting. But clinical science has to move ahead from ideas that cannot be supported at key points after decades of research.

The Long Goodbye to Glycine-Extended Peptide Hormones

“…The suggestion was based on growth studies of a cell line from a rat pancreatic cancer, ARH-2J [6]. The report stimulated studies of the growth effect of mainly glycine-extended gastrin and its homolog, the glycineextended cholecysto kinin (CCK; for review, see [8] including a number of experienced receptor laboratories, could not demonstrate specific receptors or receptor mechanisms for glycineextended gastrins and CCKs. And as often happens with negative results, the failure to identify a specific receptor has not been published, and the discussion therefore skewed and unbalanced.…”

“…Four years ago, the editors of the present journal asked for a review article addressing the question: 'Do glycine-extended hormone pre cursors have clinical significance?' The review [8] -called 'Management Perspective' -stated first that nobody questions the biosynthetic significance of glycine-extended peptides as important intracellular-processing intermediates in the cellular synthesis of α-amidated peptide hormones, and second that neither does anyone question the fact that glycine-extended precursors are often released extracellularly following endocrine, paracrine or autocrine routes of secretion. The amount of released glycine-extended peptides varies considerably, however, depending on hormone system, on its anatomical location, its phylo-and onto-genetic development and of course on the nature and magnitude of the secretory stimulus.…”

“…First, after nearly a quarter of a century of quite intensive research, there is still no convincing evidence of specific high-affinity receptors for glycine-extended peptides. Second, beyond gastrin, CCK and adrenomedullin, there has not been particular endocrine or oncological interest in extracellular glycine-extended precursors among the many other α-amidated hormones [8]. In addition, a bibliometric evaluation of publications about glycine-extended peptides in the period from 1983 to 2013 showed that the interest in later years was dwindling [8].…”

“…Second, beyond gastrin, CCK and adrenomedullin, there has not been particular endocrine or oncological interest in extracellular glycine-extended precursors among the many other α-amidated hormones [8]. In addition, a bibliometric evaluation of publications about glycine-extended peptides in the period from 1983 to 2013 showed that the interest in later years was dwindling [8]. Thus, further research in the area was apparently not to be encouraged.…”

“…According to the editorial office, the review about glycine-extended precursors [8] has nevertheless aroused interest to a degree that it has become "one of our most highly read articles in recent years" (personal letter from the Editor). So, the question now is whether the apparent decline in publications from 2006 to 2013 has continued, or whether new discoveries after 2013 have brought glycine-extended hormone precursors back into clinical focus.…”