Mevalonate-regulated mechanisms in cell growth control: role of dolichyl phosphate in expression of the insulin-like growth factor-1 receptor (IGF-1R) in comparison to Ras prenylation and expression of c-myc

Abstract

One or more mevalonate derivatives of non-sterol type have been proposed to be of indispensable importance for cell growth. Conceivable mevalonate-dependent mechanisms involved in growth control are farnesylation of Ras proteins, regulation of c-myc expression, and N-linked glycosylation of the IGF-1 receptor. The latter mechanism might be rate-limited by dolichyl phosphate, which acts as a donor of oligosaccharides in glycoprotein synthesis in the endoplasmic reticulum. In order to study the significance for cell proliferation of the three aforementioned mevalonate-dependent processings, their inhibitory response due to mevalonate deprivation was explored and compared with the effect on DNA synthesis in the malignant melanoma cell line SK-MEL-2. We found that mevalonate depletion due to treatment with 3 microM lovastatin for 24 h, which efficiently growth-arrested the cells, hardly at all affected the expression of c-myc, and although Ras prenylation was inhibited by 50%, the most pronounced effect of lovastatin was seen on N-linked glycosylation of IGF-1 receptors, which was inhibited by more than 95%. The order and magnitude of the decreased IGF-1 receptor glycosylation, which was followed by a decreased expression of IGF-1 receptors at the cell membrane, correlated well with the inhibition of DNA synthesis. We investigated whether dolichol, and in particular dolichyl phosphate, through its participation in N-linked glycosylation, act as regulators of IGF-1 receptor expression. First, we could confirm that exogenous dolichol became phosphorylated and in this form took part in the glycosylation processing. Secondly, we showed that dolichyl phosphate, in a dose-dependent manner, could increase the number of IGF-1 receptors at the cell membrane, simultaneously as DNA synthesis was stimulated. Taken together, our results provide direct evidence for an important role of dolichyl phosphate as a regulator of cell growth through limiting N-linked glycosylation of the IGF-1 receptor.

Differential expression of proliferative, cytoskeletal, and adhesive proteins during postnatal development of the hamster submandibular gland

“…6). Furthermore, recent studies suggest that dolichol phosphate, one of the substrates of GPT, is a regulator of cell growth by affecting N-glycosylation of the IGF-1 receptor (Dricu et al 1997). Taken together, these results align high levels of GPT expression with proliferation of immature salivary cells, and confirm our previously reported RNA blotting and GPT activity studies (Mota et al 1994).…”

Abrogation of Insulin-like Growth Factor-I (IGF-I) and Insulin Action by Mevalonic Acid Depletion

“…Similar results have been obtained with lovastatin. In SK-MEL-2 cells, mevalonate depletion by lovastatin resulted in Ras prenylation being inhibited by 50% (47). Lovastatin also induced apoptosis in malignant mesothelioma cell lines, which was partially reversed by farnesol refeeding (48).…”

Statin myopathy: Incidence, risk factors, and pathophysiology

“…In addition to cholesterol, there are other important downstream products of mevalonate in this molecular pathway, and evidence suggests that just as cholesterol production is decreased, production of isoprene intermediates may also be decreased [1,21]. Decreases in isoprene availability may, in turn, decrease protein prenylation, leading to alterations in important cellular processes such as N-linked glycosylation [47], electron-transport in the mitochondrial membrane [42], and cell signaling at the sarcolemma [48]. Protein prenylation is a post-translational lipid modification.…”