title: 67-kDa laminin receptor-dependent protein phosphatase 2A (PP2A) activation elicits melanoma-specific antitumor activity overcoming drug resistance.
abstract: The Ras/Raf/MEK/ERK pathway has been identified as a major, druggable regulator of melanoma. Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, resulting in constitutive melanoma hyperproliferation. A selective BRAF inhibitor showed remarkable clinical activity in patients with mutated BRAF. Unfortunately, most patients acquire resistance to the BRAF inhibitor, highlighting the urgent need for new melanoma treatment strategies. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibits cell proliferation independently of BRAF inhibitor sensitivity, suggesting that increased understanding of the anti-melanoma activity of EGCG may provide a novel therapeutic target. Here, by performing functional genetic screening, we identified protein phosphatase 2A (PP2A) as a critical factor in the suppression of melanoma cell proliferation. We demonstrated that tumor-overexpressed 67-kDa laminin receptor (67LR) activates PP2A through adenylate cyclase/cAMP pathway eliciting inhibitions of oncoproteins and activation of tumor suppressor Merlin. Activating 67LR/PP2A pathway leading to melanoma-specific mTOR inhibition shows strong synergy with the BRAF inhibitor PLX4720 in the drug-resistant melanoma. Moreover, SET, a potent inhibitor of PP2A, is overexpressed on malignant melanoma. Silencing of SET enhances 67LR/PP2A signaling. Collectively, activation of 67LR/PP2A signaling may thus be a novel rational strategy for melanoma-specific treatment.
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Tsukamoto
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Umeda
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamada
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Kumazoe
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Motoki
authors.initials: M
authors.lastname: Murata
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture and Food Functional Design Research Center, Kyushu University, Fukuoka 812-8581, Japan tatibana@agr.kyushu-u.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tachibana
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017474:Receptors, Laminin / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D007211:Indoles; D025581:Neurofibromin 2; C528407:PLX 4720; D017474:Receptors, Laminin; C513473:SET protein, human; D013449:Sulfonamides; D014157:Transcription Factors; D002392:Catechin; C045651:epigallocatechin gallate; C546842:MTOR protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2
keywords: Adenylate Cyclase (Adenylyl Cyclase); Cancer Chemoprevention; Melanoma; Membrane Protein; Polyphenol; Protein Phosphatase 2 (PP2A); Second Messenger