Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy

Abstract

Resveratrol is a plant-derived polyphenol that promotes health and disease resistance in rodent models, and extends lifespan in lower organisms. A major challenge is to understand the biological processes and molecular pathways by which resveratrol induces these beneficial effects. Autophagy is a critical process by which cells turn over damaged components and maintain bioenergetic requirements. Disruption of the normal balance between pro- and anti-autophagic signals is linked to cancer, liver disease, and neurodegenerative disorders. Here we show that resveratrol attenuates autophagy in response to nutrient limitation or rapamycin in multiple cell lines through a pathway independent of a known target, SIRT1. In a large-scalein vitro kinase screen we identified p70 S6 kinase (S6K1) as a target of resveratrol. Blocking S6K1 activity by expression of a dominant-negative mutant or RNA interference is sufficient to disrupt autophagy to a similar extent as resveratrol. Furthermore, co-administration of resveratrol with S6K1 knockdown does not produce an additive effect. These data indicate that S6K1 is important for the full induction of autophagy in mammals and raise the possibility that some of the beneficial effects of resveratrol are due to modulation of S6K1 activity.

Resveratrol induces autophagy through death‐associated protein kinase 1 (DAPK1) in human dermal fibroblasts under normal culture conditions

“…Little is known about the relationship between autophagy and skin (13,23,24). Here, we provide a new perspective on the molecular mechanism of autophagy in skin.…”

“…Mice fed with resveratrol show similar patterns with dietary restriction, exhibiting lifespan extension (9,10). Resveratrol also contributes to protection against senescence-associated gene expression changes in human dermal fibroblasts (HDFs) (11,12) and suppresses autophagy through the inhibition of p70 S6 kinase (S6K1) under serum-free condition (13). However, it remains unknown whether resveratrol affects autophagy in HDFs under normal culture conditions.…”

The regulation of autophagy – unanswered questions

“…In mammals, the TORC1 substrate S6K1 (Armour et al, 2009) is a positive regulator of autophagy, whereas yeast Sch9 is a negative regulator (Yorimitsu et al, 2007). Akt is an upstream negative regulator of the TSC1-TSC2 complex within the TOR signaling pathways that are involved in autophagy regulation in mammals and Drosophila (Dutta and Baehrecke, 2008); however, the role of Akt in autophagy is not clear in C. elegans (Kang and Avery, 2010).…”

Calorie restriction: Decelerating mTOR-driven aging from cells to organisms (including humans)

“…1). Sirtuins and their activator resveratrol, which extends life span, [60][61][62][63][64][65] antagonize the mTOR/S6K pathway [66][67][68] in part via activation of AMPK. 69,70 In addition, CR may deactivate mTOR by deactivating the insulin/PI-3K pathway.…”