title: BRAF-mutated cells activate GCN2-mediated integrated stress response as a cytoprotective mechanism in response to vemurafenib.
abstract: In BRAF-mutated melanoma cells, the BRAF inhibitor, vemurafenib, induces phosphorylation of eukaryotic initiation factor 2α (eIF2α) and subsequent induction of activating transcription factor 4 (ATF4), the central regulation node of the integrated stress response (ISR). While the ISR supports cellular adaptation to various stresses, the role of vemurafenib-triggered ISR has not been fully characterized. Here, we showed that in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2α kinase sensing amino acid levels. The vemurafenib-triggered ISR, an event independent of downstream MEK inhibition, was specifically prevented by silencing GCN2, but not other eIF2α kinases, including protein kinase-like endoplasmic reticulum kinase, which transmits endoplasmic reticulum (ER) stress. Consistently, the ER stress gatekeeper, GRP78, was not induced by vemurafenib. Interestingly, ATF4 silencing by siRNA rendered BRAF-mutated melanoma cells sensitive to vemurafenib. Thus, the GCN2-mediated ISR can promote cellular adaptation to vemurafenib-induced stress, providing an insight into the development of drug resistance.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan; Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nagasawa
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kunimasa
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan; Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan. Electronic address: akihiro.tomida@jfcr.or.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008545:Melanoma / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry*; D000077484:Vemurafenib; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007211:Indoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051701:Activating Transcription Factor 4; D000077484:Vemurafenib; C482119:BRAF protein, human; C460640:EIF2AK3 protein, human; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D019892:eIF-2 Kinase
keywords: 2-Deoxy-d-glucose (PubChem CID: 45038823); ATF4; BRAF; Dabrafenib (PubChem CID: 44462760); GCN2; GSK2656157 (PubChem CID: 53469059); Integrated stress response; Trametinib (PubChem CID: 11707110); Tunicamycin (PubChem CID: 16220051); Vemurafenib; Vemurafenib (PubChem CID: 42611257)