title: Midkine confers Adriamycin resistance in human gastric cancer cells.
abstract: Midkine (MDK) is a heparin-binding molecule involved in the regulation of growth and differentiation during embryogenesis, which is overexpressed in most of human malignant tumors and may act as an oncoprotein. The aim of the current study was to investigate the mechanism of MDK involved in the Adriamycin (ADR) resistance in human gastric cancer cells in vitro. We found that Adriamycin-resistant SGC7901 (SGC7901/ADR) exhibited 58.6-fold greater resistance to ADR compared with Adriamycin-sensitive SGC7901 cell line. MDK mRNA and protein expression levels were significantly higher in SGC7901/ADR than in SGC7901. To gain a deeper insight into the role of MDK in SGC7901/ADR, we stably transfected Adriamycin-sensitive SGC7901 with viral vector expressing MDK. Our result showed that multidrug resistance type I (MDR1) was found in SGC7901/ADR, not in SGC7901 by RT-PCR regardless of MDK transfection. P-Glycoprotein, which is the MDR1-coded protein, was found in SGC7901/ADR, not in SGC7901 by Western blot regardless of MDK transfection. We investigated whether an activation of the tyrosine kinase pathway would change the drug resistance phenotype with MDK transfection. Western blot results showed the upregulation of phosphorylated protein kinase B (AKT) and phosphorylated extracellular signal-regulated protein kinase (ERK) in Adriamycin-sensitive SGC7901 cell by MDK transfection accompanied with drug resistance to ADR, although the level of AKT and ERK protein expression did not change, so our results suggested that MDK, which can activate AKT and ERK by phosphorylation, induced the Adriamycin resistance in gastric cancer cells. Understanding the molecular mechanisms, driving MDK-induced ADR resistance, will provide benefits in developing new therapies for gastric cancer.
authors.affiliation: Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110001, People's Republic of China.
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Xu
authors.forename: Xiao-yun
authors.initials: XY
authors.lastname: Mao
authors.forename: Yong-xi
authors.initials: YX
authors.lastname: Song
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Zhen-ning
authors.initials: ZN
authors.lastname: Wang
authors.forename: Wei-xu
authors.initials: WX
authors.lastname: Zhang
authors.forename: Hui-mian
authors.initials: HM
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D000078792:Midkine; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D000078792:Midkine; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases