Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin

被引:86
|
作者
Cui, Hongyan
Darmanin, Stephanie
Natsuisaka, Mitsuteru
Kondo, Takeshi
Asaka, Masahiro
Shindoh, Masanobu
Higashino, Fumihiro
Hamuro, Junji
Okada, Futoshi
Kobayashi, Masataka
Nakagawa, Koji
Koide, Hideyuki
Kobayashi, Masanobu
机构
[1] Oncorex Inc, Kita Ku, Sapporo, Hokkaido, Japan
[2] Hokkaido Univ, Dept Pathol Oncol, Div Canc, Grad Sch Med, Sapporo, Hokkaido 060, Japan
[3] Hokkaido Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Sapporo, Hokkaido 060, Japan
[4] Hokkaido Univ, Dept Oral Pathobiol Sci, Grad Sch Dent Med, Sapporo, Hokkaido 060, Japan
[5] Hokkaido Univ, Div Canc Biol, Inst Med Genet, Sapporo, Hokkaido 060, Japan
[6] Keio Univ Med, Dept Microbiol & Immunol, Tokyo, Japan
[7] Yamagata Univ, Grad Sch Med Sci, Dept Biomol Funct, Yamagata 990, Japan
关键词
D O I
10.1158/0008-5472.CAN-06-2519
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 NH2-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.
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收藏
页码:3345 / 3355
页数:11
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