title: Protection of stromal cell-derived factor 2 by heat shock protein 72 prevents oxaliplatin-induced cell death in oxaliplatin-resistant human gastric cancer cells.
abstract: Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers.
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan; Department of Pharmacy, Osaka City University Hospital, Osaka, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Ohtsuka
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Department of Pharmacy, Osaka City University Hospital, Osaka, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagayama
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan; Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. Electronic address: sio@med.osaka-cu.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shiota
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D055550:Protein Stability; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D050884:HSP72 Heat-Shock Proteins; D009944:Organoplatinum Compounds; D011506:Proteins; C102467:SDF2 protein, human; D000077150:Oxaliplatin
keywords: Drug resistance; Heat shock protein 72; Oxaliplatin