Normal human melanocytes exposed to chronic insulin and glucose supplementation undergo oncogenic changes and methyl group metabolism cellular redistribution.

Daniel Morvan 1, 2 Jean Marc Steyaert 3, 4 Laurent Schwartz 5, 4 Maurice Israel 6 Aicha Demidem
3 AMIB - Algorithms and Models for Integrative Biology
CNRS - Centre National de la Recherche Scientifique : UMR8623, Polytechnique - X, Inria Saclay - Ile de France, UP11 - Université Paris-Sud - Paris 11, LRI - Laboratoire de Recherche en Informatique, LIX - Laboratoire d'informatique de l'École polytechnique [Palaiseau]
Abstract : Recent epidemiological studies have suggested a link between cancer and pathophysiological conditions associated with hyperinsulinemia. In this report, we address the possible role of insulin exposure in melanocyte transformation. To this aim, normal melanocytes were exposed to chronic insulin and glucose supplementation (twice the standard medium concentration) for at least 3 wk. After 3-wk treatment, melanocytes increased proliferation (doubling time: 2.7 vs. 5.6 days, P < 0.01). After 3-wk treatment or after 3-wk treatment followed by 4-wk reculture in standard medium, melanocytes were able to grow in soft agar colonies. Treated melanocytes had increased DNA content (+8%, P < 0.05), chromosomal aberrations, and modified oncoprotein profile: p-Akt expression increased (+32%, P < 0.01), Akt decreased, and c-Myc increased (+40%, P < 0.05). PP2A protein expression increased (+42, P < 0.05), while PP2A methylation decreased (-42%, P < 0.05), and PP2A activity was reduced (-27%, P < 0.05). PP2A transcription level was increased (ppp2r1a, PP2A subunit A, +44%, P < 0.05). Also, transcriptomic data revealed modifications in insr (insulin receptors, +10%, P < 0.05) and Il8 (inflammation protein, +99%, P < 0.01). Glycolysis was modified with increased transcription of Pgk1 and Hif1a (P < 0.05), decreased transcription of Pfkfb3 (P < 0.05), decreased activity of pyruvate kinase (P < 0.01), and decreased pyruvate cell content as assessed by (1)H-NMR spectroscopy. In addition, methyl group metabolism was altered with decreased global DNA methylation (-51%, P < 0.01), increased cytosolic protein methylation (+18%, P < 0.05), and consistent changes in methylated species on (1)H-NMR spectra. In conclusion, exposure to chronic insulin and glucose supplementation induces oncogenic changes and methyl group metabolism redistribution, which may be a biomarker of transformation.
Type de document :
Article dans une revue
AJP - Endocrinology and Metabolism, American Physiological Society, 2012, 302 (11), pp.E1407-18. 〈10.1152/ajpendo.00594.2011〉
Liste complète des métadonnées

https://hal.inria.fr/hal-00761765
Contributeur : Julie Bernauer <>
Soumis le : jeudi 6 décembre 2012 - 10:10:09
Dernière modification le : jeudi 11 janvier 2018 - 06:23:32

Identifiants

Citation

Daniel Morvan, Jean Marc Steyaert, Laurent Schwartz, Maurice Israel, Aicha Demidem. Normal human melanocytes exposed to chronic insulin and glucose supplementation undergo oncogenic changes and methyl group metabolism cellular redistribution.. AJP - Endocrinology and Metabolism, American Physiological Society, 2012, 302 (11), pp.E1407-18. 〈10.1152/ajpendo.00594.2011〉. 〈hal-00761765〉

Partager

Métriques

Consultations de la notice

375