Premium
Resveratrol‐Mediated Downregulation of Rictor Attenuates Autophagic Process and Suppresses UV‐Induced Skin Carcinogenesis †
Author(s) -
Back Jung H.,
Zhu Yucui,
Calabro Alyssa,
Queenan Craig,
Kim Audrey S.,
Arbesman Joshua,
Kim Arianna L.
Publication year - 2012
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.2012.01097.x
Subject(s) - microbiology and biotechnology , resveratrol , downregulation and upregulation , autophagy , autophagosome , biology , rhoa , senescence , mtorc2 , chemistry , mtorc1 , pi3k/akt/mtor pathway , biochemistry , signal transduction , apoptosis , gene
Macroautophagy is a cellular response to various environmental stresses that ensures lysosomal degradation of long‐lived and damaged proteins and cellular organelles. It occurs through the formation of an autophagosome, which then fuses with a lysosome to form an autolysosome. Depending on the cellular context, autophagy may promote cancer cell survival or it may serve as a mechanism of tumor suppression. Herein, we show that resveratrol, a natural phytoalexin, induces premature senescence in human A431 SCC cells, and that resveratrol‐induced premature senescence is associated with a blockade of autolysosome formation, as assessed by the absence of colocalization of LC3 and Lamp‐2, markers for autophagosomes and lysosomes, respectively. Further, we show that resveratrol downregulates the level of Rictor, a component of mTORC2, leading to decreased RhoA‐GTPase and altered actin cytoskeleton organization. Exogenous overexpression of Rictor restores RhoA‐GTPase activity and actin cytoskeleton network, and decreases resveratrol‐induced senescence‐associated β‐gal activity, indicating a direct role of Rictor in senescence induction. Rictor is overexpressed in UV‐induced murine SCCs, whereas its expression is diminished by oral administration of resveratrol. These data indicate that resveratrol attenuates autophagic process via Rictor, and suggest that downregulation of Rictor may be a mechanism of tumor suppression associated with premature senescence.