title: BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells.
abstract: Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells.
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Sueda
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sakai
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Konno
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hugh
authors.initials: H
authors.lastname: Colvin
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Haraguchi
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.affiliation: Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007279:Injections, Subcutaneous; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D055372:AMP-Activated Protein Kinases