ABSTRACT
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 ß-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.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Squamous Cell/drug therapy , Carrier Proteins/antagonists & inhibitors , Skin Neoplasms/drug therapy , Skin/drug effects , Stilbenes/pharmacology , Animals , Autophagy/drug effects , Autophagy/radiation effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Cellular Senescence/drug effects , Cellular Senescence/radiation effects , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/radiation effects , Humans , Lysosomal-Associated Membrane Protein 2/genetics , Lysosomal-Associated Membrane Protein 2/metabolism , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Hairless , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Phagosomes/drug effects , Phagosomes/radiation effects , Rapamycin-Insensitive Companion of mTOR Protein , Resveratrol , Signal Transduction/drug effects , Signal Transduction/radiation effects , Skin/pathology , Skin/radiation effects , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Ultraviolet RaysABSTRACT
Deregulated mTOR signaling drives the growth of various human cancers, making mTOR a major target for development of cancer chemotherapeutics. The role of mTOR in carcinogenesis is thought to be largely a consequence of its activity in the cytoplasm resulting in increased translation of pro-tumorigenic genes. However, emerging data locate mTOR in various subcellular compartments including Golgi, mitochondria, endoplasmic reticulum, and the nucleus, implying the presence of compartment-specific mTOR substrates and functions. Efforts to identify mTOR substrates in these compartments, and the mechanisms by which mTOR recruits these substrates and affects downstream cellular processes, will add to our understanding of the diversity of roles played by mTOR in carcinogenesis.
