Subhi Ahmad L, Tang Baiqing, Balsara Binaifer R, Altomare Deborah A, Testa Joseph R, Cooper Harry S, Hoffman John P, Meropol Neal J, Kruger Warren D
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clin Cancer Res. 2004 Nov 1;10(21):7290-6. doi: 10.1158/1078-0432.CCR-04-0972.
Loss of the methylthioadenosine phosphorylase (MTAP) gene at 9p21 is observed frequently in a variety of human cancers. We have shown previously that MTAP can act as a tumor suppressor gene and that its tumor suppressor function is related to its effect on polyamine homeostasis. Ornithine decarboxylase is a key enzyme in the regulation of polyamine metabolism. The aim of this study is to analyze MTAP and ornithine decarboxylase (ODC) expression in primary pancreatic tumor specimens.
We measured MTAP and ODC activity in protein extracts derived from 30 surgically resected tumor samples and eight normal pancreas samples. In a subset of six samples, we also examined MTAP DNA using interphase fluorescence in situ hybridization. In addition, we examined the effect of the ODC inhibitor difluoromethylornithine on two pancreatic adenocarcinoma-derived cell lines.
MTAP activity was 2.8-fold reduced in adenocarcinomas and 6.3-fold reduced in neuroendocrine tumors compared with control pancreas. Conversely, ODC activity was 3.6-fold elevated in adenocarcinomas and 3.9-fold elevated in neuroendocrine tumors compared with control pancreas. Using interphase fluorescence in situ hybridization, we found in tumor samples that 43 to 75% of the nuclei had lost at least one copy of MTAP locus, indicating that loss of MTAP activity was at least partially because of deletion of the MTAP locus. We also show that inhibition of ODC by difluoromethylornithine caused decreased cell growth and increased apoptosis in two MTAP-deleted pancreatic adenocarcinoma-derived cell lines.
MTAP activity is frequently lost, and ODC activity is frequently elevated in both pancreatic adenocarcinoma and neuroendocrine tumors. Inhibition of ODC activity caused decreased cell growth and increased apoptosis in pancreatic tumor-derived cell lines. These findings suggest that MTAP and polyamine metabolism could be potential therapeutic targets in the treatment of pancreatic cancer.
9p21处甲硫腺苷磷酸化酶（MTAP）基因缺失在多种人类癌症中频繁出现。我们之前已经表明MTAP可作为一种肿瘤抑制基因，并且其肿瘤抑制功能与其对多胺稳态的影响有关。鸟氨酸脱羧酶是多胺代谢调节中的关键酶。本研究的目的是分析原发性胰腺肿瘤标本中MTAP和鸟氨酸脱羧酶（ODC）的表达。
我们测量了来自30个手术切除的肿瘤样本和8个正常胰腺样本的蛋白质提取物中的MTAP和ODC活性。在6个样本的子集中，我们还使用间期荧光原位杂交检测了MTAP DNA。此外，我们研究了ODC抑制剂二氟甲基鸟氨酸对两种胰腺腺癌衍生细胞系的影响。
与对照胰腺相比，腺癌中MTAP活性降低了2.8倍，神经内分泌肿瘤中降低了6.3倍。相反，与对照胰腺相比，腺癌中ODC活性升高了3.6倍，神经内分泌肿瘤中升高了3.9倍。使用间期荧光原位杂交，我们在肿瘤样本中发现43%至75%的细胞核至少丢失了一个MTAP基因座拷贝，表明MTAP活性的丧失至少部分是由于MTAP基因座的缺失。我们还表明，二氟甲基鸟氨酸抑制ODC会导致两种MTAP缺失的胰腺腺癌衍生细胞系的细胞生长减少和凋亡增加。
在胰腺腺癌和神经内分泌肿瘤中，MTAP活性经常丧失，ODC活性经常升高。抑制ODC活性会导致胰腺肿瘤衍生细胞系的细胞生长减少和凋亡增加。这些发现表明MTAP和多胺代谢可能是胰腺癌治疗中的潜在治疗靶点。
