Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin
Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin
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DOI：
10.1158/0008-5472.can-06-2519
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Kobayashi, Masanobu
中科院分区：
文献类型：
--
作者：
Cui, Hongyan;Darmanin, Stephanie;Kobayashi, Masanobu
虽然低血管是胰腺癌的突出特征，但肿瘤细胞在由低血供引起的严重缺氧、缺糖条件下存活和增殖。众所周知，缺氧诱导因子-1通路对于胰腺癌细胞在缺氧条件下的存活是必需的。为了发现胰腺癌细胞如何适应葡萄糖剥夺以及缺氧，我们通过DNA微阵列系统寻找葡萄糖剥夺诱导基因。我们鉴定了63个基因，其表达在葡萄糖剥夺条件下以比正常葡萄糖条件下高2倍的水平增强。在这些基因中，天冬酰胺合成酶（ASNS）进行了详细的研究。虽然已知它与白血病的耐药性和由突变的p53引发的肿瘤发生有关，但其功能尚未确定。在本研究中，我们发现，葡萄糖剥夺诱导ASNS的过度表达，通过AMP激活的蛋白激酶依赖和激活转录因子4依赖的方式和ASNS保护胰腺癌细胞凋亡诱导葡萄糖剥夺本身。ASNS过表达还诱导对顺铂[顺二氨二氯铂（CDDP）]和卡铂触发的细胞凋亡的抵抗，但不诱导对5-氟尿嘧啶、紫杉醇、依托泊苷或吉西他滨触发的细胞凋亡的抵抗。我们发现，葡萄糖剥夺诱导c-jun NH 2-末端激酶（JNK）/应激激活蛋白激酶（SAPK）在模拟转染，但不是在ASNS转染激活。因此，JNK/SAPK的抑制剂降低了胰腺癌细胞对葡萄糖剥夺和CDDP引起的凋亡的敏感性。这些结果有力地表明，ASNS是由葡萄糖剥夺诱导的，并且可能在葡萄糖剥夺条件下胰腺癌细胞的存活中起关键作用。
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.