Global Transcript Changes In Human Keratinocyte Cells Induced by Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors

To elucidate the mode of action of apratyramide, we performed microarray profiling using the Affymetrix GeneChip Human Transcriptome Array 2.0 to determine global changes in transcript levels in HaCaT cells treated with apratyramide. Comparativel analysis identified 371 differentially expressed genes after 12 h treatment with 30 M apratyramide (p < 0.05, FDR corrected, fold change >1.5 or <0.67). Consistent with our previous data, VEGF-A appeared to be one of the most up-regulated genes. To examine the molecular functions and genetic networks, the microarray data was analyzed using Ingenuity Pathways Aanalysis (IPA).The global changes of transcript levels are associated with increased downstream phenotypic effects including angiogenesis, mitogenesis, differentiation of epithelial tissue and formation of skin, and decreased effects such as apoptosis of liver cells and hypoplasia of organs. IPA analysis of 371 microarray hits indicated the unfolded protein response (UPR) as the top canonical pathway with a p-value of 1.45 10-16. The IPA also elucidated that the 371 hits were most related to a molecular network associated with the function of cellular compromise and cellular maintenance. The network contains molecular components from UPR pathway, NRF2-mediated oxidative stress response signaling as well as glucocorticoid receptor signaling.

8

Cai W, Salvador-Reyes LA, Zhang W, Chen QY, Matthew S, Ratnayake R, Seo SJ, Dolles S, Gibson DJ, Paul VJ, Luesch H