title: GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS axis in hepatocellular carcinoma.
abstract: 5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.
authors.affiliation: Pathology Department, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China.
authors.forename: Yan-jiao
authors.initials: YJ
authors.lastname: Gu
authors.affiliation: Central Laboratory, Liaoning Medical College, Jinzhou, China.
authors.forename: Hong-dan
authors.initials: HD
authors.lastname: Li
authors.affiliation: Central Laboratory, Liaoning Medical College, Jinzhou, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Pharmacy Department, Liaoning Medical College, Jinzhou, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Pathology Department, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China.
authors.forename: Wu-bin
authors.initials: WB
authors.lastname: He
authors.affiliation: Pathology Department, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Rui
authors.affiliation: Veterinary Medicine Department, Liaoning Medical College, Jinzhou, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Su
authors.affiliation: Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China.
authors.forename: Hua-chuan
authors.initials: HC
authors.lastname: Zheng
authors.affiliation: Central Laboratory, Liaoning Medical College, Jinzhou, China.
authors.forename: Rong-jian
authors.initials: RJ
authors.lastname: Su
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015398:Signal Transduction; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C501906:TFCP2 protein, human; D014157:Transcription Factors; D013940:Thymidylate Synthase; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D005472:Fluorouracil
keywords: 5-FU; GRP78; LSF; TS; chemoresistance