Abstract
DAF-16 target genes are employed as reporters of the insulin/IGF-1 like signal pathway (IIS), and this is notably true when Caenorhabditis elegans (C. elegans) is used to study the action of anti-aging compounds on IIS activity. However, some of these genes may not be specific to DAF-16, even if their expression levels are altered when DAF-16 is activated. Celecoxib was reported to extend the lifespan of C. elegans through activation of DAF-16. Our results confirmed the function of celecoxib on aging; however, we found that the expression of ins-7, a DAF-16 target gene, was abnormally regulated by celecoxib. ins-7 plays an important role in regulating aging, and its expression is suppressed in C. elegans when DAF-16 is activated. However, we found that celecoxib upregulated the expression of ins-7 in contrast to its role in DAF-16 activation. Our subsequent analysis indicated that the expression level of ins-7 in C. elegans was negatively regulated by DAF-16 activity. Additionally, its expression was also positively regulated by DAF-16-independent mechanisms, at least following external pharmacological intervention. Our study suggests that ins-7 is not a specific target gene of DAF-16, and should not be chosen as a reporter for IIS activity. This conclusion is important in the study of INSs on aging in C. elegans, especially under the circumstance of drug intervention.
Highlights
From invertebrates to vertebrates, the insulin/IGF-1-like signaling pathway (IIS) is evolutionary conservation and plays an important role in regulating animal development and pathology [1,2,3,4]
Celecoxib extends the lifespan of C. elegans by decreasing IIS signal transduction, which serves to activate DAF-16 [19]
Our results indicated that celecoxib had no effect on the lifespan of daf-16 I worms (Figure 1B, Table 1)
Summary
The insulin/IGF-1-like signaling pathway (IIS) is evolutionary conservation and plays an important role in regulating animal development and pathology [1,2,3,4]. Phosphatidylinositol 3-kinase (PI3K) is activated to generate phosphatidylinositol 3, 4, 5-triphosphate (PIP3) when the cell membrane-localized IIS receptor is stimulated by insulin or IGF-1. Protein kinase B (PKB) is localized to the cell membrane by PIP3 and activated by PDK-1/2 to phosphorylate FOXO transcription factors [5]. In C. elegans, insulin-like proteins activate the PI3K homolog AGE-1 through the IIS receptor DAF-2, directing the AKT-1/2 and SGK-1 kinases to phosphorylate the FOXO protein DAF-16 with phosphorylated DAF-16 accumulating in the nuclei [6]. Decreased IIS signal transduction releases the FOXO protein DAF-16 into the nucleus to regulate the expression levels of many genes
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