title: Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism.
abstract: Bortezomib is an anti-cancer agent that induces ER stress by inhibiting proteasomal degradation. However, the effects of bortezomib appear to be dependent on its concentration and cellular context. Since ER stress is closely related to type 2 diabetes, the authors examined the effects of bortezomib on palmitic acid (PA)-induced ER stress in C2C12 murine myotubes. At low concentrations (<20nM), bortezomib protected myotubes from PA (750μM)-induced ER stress and inflammation. Either tunicamycin or thapsigargin-induced ER stress was also reduced by bortezomib. In addition, reduced glucose uptake and Akt phosphorylation induced by PA were prevented by co-treating bortezomib (10nM) both in the presence or absence of insulin. These protective effects of bortezomib were found to be associated with reduced JNK phosphorylation. Furthermore, bortezomib-induced AMPK phosphorylation, and the protective effects of bortezomib were diminished by AMPK knockdown, suggesting that AMPK activation underlies the effects of bortezomib. The in vivo administration of bortezomib at nontoxic levels (at 50 or 200μg/kg, i.p.) twice weekly for 5weeks to ob/ob mice improved insulin resistance, increased AMPK phosphorylation, reduced ER stress marker levels, and JNK inhibition in skeletal muscle. The study shows that bortezomib reduces ER stress, inflammation, and insulin resistance in vitro and in vivo, and suggests that bortezomib has novel applications for the treatment of metabolic disorders.
authors.affiliation: Department of Pharmacology, Gachon University School of Medicine, Incheon 406-799, Republic of Korea.
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Kwak
authors.affiliation: Department of Pharmacology, Gachon University School of Medicine, Incheon 406-799, Republic of Korea.
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Gachon University School of Medicine, Incheon 406-799, Republic of Korea.
authors.forename: Jinsun
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, Gachon University School of Medicine, Incheon 406-799, Republic of Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Microbiology, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Young-An
authors.initials: YA
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, Gachon University School of Medicine, Incheon 406-799, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Incheon 405-760, Republic of Korea. Electronic address: hgcheon@gachon.ac.kr.
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology*; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000473:pathology*; D007333:Insulin Resistance; D008297:Male; D008820:Mice, Obese; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology*; D019308:Palmitic Acid / Q000633:toxicity*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D014415:Tunicamycin; D019308:Palmitic Acid; D019284:Thapsigargin; D000069286:Bortezomib; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Bortezomib; ER stress; Insulin resistance; Myotube