Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines.

Physiologically, the action of insulin-like growth factors (IGFs) is controlled at different levels, from its transcription start by tissue-specific and development-specific transcriptional factors to its degradation by peptidases such as insulin-degrading enzyme (IDE). Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system. Here, we show that (a) IDE is expressed in several human neuroectodermal tumor cell lines, including neuroblastoma cell lines; (b) in a neuroblastoma cell line, IDE expression is up-regulated by retinoic acid, a well-known inducer of neuronal differentiation and/or programmed cell death; (c) IDE is probably not the only IGF-degrading enzyme present in these cells, since the activity of a novel thermolysin-like metalloendopeptidase, clearly distinct from IDE, is also detected. The TME activity is inhibited by IGF-I, Des-IGF-I, and IGF-II, and it is down-regulated by retinoic acid. Since retinoic acid plays a relevant role in controlling the growth of these cells and affects the expression of IDE, we have also: (a) identified the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) expressed in these cell lines and (b) by means of synthetic retinoid analogues identified the RAR/RXR isoforms whose activation may be sufficient to induce the expression of the IDE gene. These results provide evidence that complex posttranslational molecular mechanisms participate in the autocrine/paracrine growth control of the IGF-II loop in neuroblastomas involving proteolytic systems.