title: Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin.
abstract: Although hypovasculature is an outstanding characteristic of pancreatic cancers, the tumor cells survive and proliferate under severe hypoxic, glucose-deprived conditions caused by low blood supply. It is well known that the hypoxia-inducible factor-1 pathway is essential for the survival of pancreatic cancer cells under hypoxic conditions. To discover how pancreatic cancer cells adapt to glucose deprivation as well as hypoxia, we sought glucose deprivation-inducible genes by means of a DNA microarray system. We identified 63 genes whose expression was enhanced under glucose-deprived conditions at >2-fold higher levels than under normal glucose conditions. Among these genes, asparagine synthetase (ASNS) was studied in detail. Although it is known to be associated with drug resistance in leukemia and oncogenesis triggered by mutated p53, its function is yet to be determined. In this study, we found that glucose deprivation induced the overexpression of ASNS through an AMP-activated protein kinase-independent and activating transcription factor-4-dependent manner and that ASNS protects pancreatic cancer cells from apoptosis induced by glucose deprivation itself. ASNS overexpression also induced resistance to apoptosis triggered by cisplatin [cis-diammine-dichloroplatinum (CDDP)] and carboplatin, but not by 5-fluorouracil, paclitaxel, etoposide, or gemcitabine. We show that glucose deprivation induces the activation of c-jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase (SAPK) in a mock transfectant but not in an ASNS transfectant. Consequently, an inhibitor of JNK/SAPK decreased the sensitivity of pancreatic cancer cells to apoptosis by glucose deprivation and CDDP. These results strongly suggest that ASNS is induced by glucose deprivation and may play a pivotal role in the survival of pancreatic cancer cells under glucose-deprived conditions.
authors.affiliation: Department of Pathological Oncology, Division of Cancer, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Cui
authors.forename: Stephanie
authors.initials: S
authors.lastname: Darmanin
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuisaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Higashino
authors.forename: Junji
authors.initials: J
authors.lastname: Hamuro
authors.forename: Futoshi
authors.initials: F
authors.lastname: Okada
authors.forename: Masataka
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Koide
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001216:Asparagine / Q000378:metabolism / Q000494:pharmacology; D001217:Aspartate-Ammonia Ligase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D001216:Asparagine; D048031:JNK Mitogen-Activated Protein Kinases; D001217:Aspartate-Ammonia Ligase; D005947:Glucose; D002945:Cisplatin; D005472:Fluorouracil