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Induction of cellular senescence represents a novel strategy to inhibit aberrant proliferation of cancer cells. Resveratrol is gaining attention for its cancer preventive and suppressive properties. Tumor suppressor gene DLC1 is shown to induce apoptosis, suppress migration and invasion in various cancer cells. However, the function of DLC1 in cancer cellular senescence is unclear. This study was designed to investigate the biological role of DLC1 in resveratrol induced cancer cellular senescence. Our results showed that resveratrol inhibited proliferation of cancer cell lines (MCF-7, MDA-MB-231 and H1299) and induced senescence along with increase of SA-β-gal activity and regulation of senescence-associated molecular markers p38MAPK, p-p38MAPK, p27, p21, Rb and p-Rb protein. The underlying mechanism was that resveratrol induced mitochondrial dysfunction with reduction of mitochondrial membrane potential, down-regulation of MT-ND1, MT-ND6 and ATPase8 in transcript level and down-regulation of PGC-1α in protein level to result in ROS production. With ROS elevation, resveratrol decreased DNMT1 and increased DLC1 expression significantly. However, after ROS scavenger NAC was added to the cancer cells treated by resveratrol, DNMT1, DLC1 and senescence-associated molecular markers were reversed. This reveals that resveratrol induced cancer cellular senescence through DLC1 in a ROS-dependent manner. Silencing DLC1 markedly attenuated SA-β-gal activity and p38MAPK, p27 and p21 protein levels, and increased Rb expression, indicating that resveratrol promoted senescence via targeting DLC1. Moreover, DLC1 promoted senescence through FoxO3a/NF-κB signaling mediated by SIRT1 after resveratrol treatment. Finally, resveratrol increased ROS production to induce DNA damage with p-CHK1 up-regulation and result in cancer cellular senescence. This is the first time to investigate resveratrol induced cancer cellular senescence by primarily targeting DLC1. Induction of cellular senescence by resveratrol may represent a novel anticancer mechanism.Representative schematic diagram summarizing the signaling pathway for cancer cellular senescence induced by resveratrol.Resveratrol stimulates senescence-associated proteins to induce cellular senescence.Resveratrol causes mitochondrial dysfunction to promote ROS production.DLC1 is essential for resveratrol induced senescence by promoting ROS production.DLC1 induces cellular senescence through FoxO3a/NF-κB signaling mediated by SIRT1.ROS production as the cause of resveratrol to induce DNA damage in cancer cells.