Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling

Abstract

Astaxanthin (AST) is a carotenoid with therapeutic values on hyperglycemia and diabetic complications. The mechanisms of action of AST remain incompletely understood. p70 S6 kinase 1 (S6K1) is a serine/threonine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)S1101 and desensitizes the insulin receptor (IR). Our present study aims to determine if AST improves glucose metabolisms by targeting S6K1. Western blot analysis revealed that AST inhibited the phosphorylation of two S6K1 substrates, S6S235/236 and IRS-1S1101, but enhanced the phosphorylation of AKTT308, AKTS473, and S6K1T389 by feedback activation of the phosphatidylinositol-3 (PI-3) kinase in 3T3-L1 adipocytes and L6 myotubes. In vitro kinase assays revealed that AST inhibited S6K1 activity with an IC50 value of approximately 13.8 μM. AST increased insulin-induced IR tyrosine phosphorylation and IRS-1 binding to the p85 subunit of PI-3 kinase. Confocal microscopy revealed that AST increased the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane in L6 cells. Glucose uptake assays using a fluorescent dye, 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose), revealed that AST increased glucose uptake in 3T3-L1 adipocytes and L6 myotubes under insulin resistance conditions. Our study identifies S6K1 as a previously unrecognized molecular target of AST and provides novel insights into the mechanisms of action of AST on IR sensitization.

Astaxanthin Protects Dendritic Cells from Lipopolysaccharide-Induced Immune Dysfunction

“…Astaxanthin, 3,3′-dihydroxy-β,β′-carotene-4,4′-dione, is a naturally occurring red carotenoid pigment classified as a xanthophyll, found in microalgae and seafood such as salmon, trout, and shrimp [ 20 , 21 ]. The lipid-soluble carotenoid, with a polar–nonpolar–polar structure, is able to help astaxanthin easily pass through and fix into the double layers of the cell membrane.…”

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

“…However, due to the negative feedback regulation of the PI3K-AKT pathway (Fig. 5A ), directly [ 211 , 221 ] or indirectly [ 244 ] targeting S6K will induce elevated AKT kinase activity, which may result in drug resistance. To this end, dual-target inhibitors for S6K and AKT have begun to be developed and display a good response in cancer therapies [ 219 , 225 ].…”

“…As a xanthophyll carotenoid, astaxanthin (AST) is a natural product mainly derived from seafoods, functioning as an inhibitor of S6K1, which is evidenced by inhibited phosphorylation of S6 and IRS1. However, administration of AST is also accompanied by enhanced phosphorylation of AKT and S6K at T389 because of abolished negative feedback regulation of S6K1 on the PI3K/AKT pathway [ 221 ]. Combining genetics with chemistry, Dar et al synthesized a series of compounds, among which AD80 and AD81 were identified as polypharmacological agents, possessing optimal balance against Ret, Src, Raf, TOR, and S6K kinase activities [ 222 ].…”

Kampo formula hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang, TJ-41) ameliorates muscle atrophy by modulating atrogenes and AMPK in vivo and in vitro

“…However, both Akt and mTOR were inhibited, suggesting the pathway was suppressed upstream of Akt. Under overnutrient conditions, p70 inhibits insulin receptor substrate-1 (IRS-1) by phosphorylation at multiple sites, negatively regulating insulin signaling [ 44 , 45 ]. This negative feedback might have inactivated Akt and mTOR on the day the mice were sacrificed.…”