LKB1 reduces ROS-mediated cell damage via activation of p38

Abstract

Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) is a tumor suppressor mutated in Peutz-Jeghers syndrome and in a variety of sporadic cancers. Herein, we demonstrate that LKB1 controls the levels of intracellular reactive oxygen species (ROS) and protects the genome from oxidative damage. Cells lacking LKB1 exhibit markedly increased intracellular ROS levels, excessive oxidation of DNA, increased mutation rates, and accumulation of DNA damage, which are effectively prevented by ectopic expression of LKB1 and by incubation with antioxidant N-acetylcysteine (NAC). The role of LKB1 in suppressing ROS is independent of AMPK, a canonical substrate of LKB1. Instead, under the elevated ROS, LKB1 binds to and maintains the activity of cdc42-PAK1 (p21 activated kinase 1) complex, which triggers the activation of p38 and its downstream signaling targets, such as ATF-2, thereby enhancing the activity of SOD-2 and catalase, two antioxidant enzymes that protect the cells from ROS accumulation, DNA damage, and loss of viability. Our results provide a new paradigm for a non-canonical tumor suppressor function of LKB1 and highlight the importance of targeting ROS signaling as a potential therapeutic strategy for cancer cells lacking LKB1.

Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

“…Recently, several preclinical studies have suggested a critical role of ROS in cancer therapy [ 8 , 11 – 15 , 19 , 32 ]. ROS regulation can modulate the cytotoxic effect of taxanes in cancer cells [ 17 , 18 ].…”

“…Recent studies shed light on the reactive oxygen species (ROS) production induced by anticancer drugs in cancer cells, which may influence the cell death or the drug resistance [ 8 – 15 ]. ROS are generated by oxidative stress and sometimes associated with the sensitivity or resistance to anticancer drugs [ 8 , 11 – 14 , 16 ].…”

“…ROS are generated by oxidative stress and sometimes associated with the sensitivity or resistance to anticancer drugs [ 8 , 11 – 14 , 16 ]. It has been reported that reduction of ROS production can modulate the cytotoxic effect of taxanes in cancer cells [ 13 , 15 , 17 – 19 ]. However, the ROS production by cabazitaxel or the mechanistic action has not characterized yet in cancer cells, including CRPC.…”

TMIGD1 is Expressed at Low Levels in Abdominal Adhesion Tissue and Reduces Oxidative Stress in Peritoneal Mesothelial Cells

“…Although a certain concentration of ROS is bene cial for tissue repair, a large amount of ROS can damage peritoneal mesothelial cells [17,19] . The p38 signaling pathway participates in many physiological processes involved in tissue healing [20] . It has been reported that p38 can promote SOD2 transcription.…”

Acetyl-macrocalin B, anent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer

“…Previous studies have shown that p38 and its downstream signaling pathway are critical responders to ROS stress, 27,28 and both ROS and p38 regulate apoptosis. 20,29 In the present study, we found that along with ROS increasing, the p38 pathway was activated by A-macB treatment, as evidenced by the increased expression of p-p38 (Thr180/Tyr182) and its downstream target p-HSP27 (Ser82) ( Fig.…”