Glucagon-like peptide-2 does not modify the growth or survival of murine or human intestinal tumor cells
Glucagon-like peptide-2 does not modify the growth or survival of murine or human intestinal tumor cells
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DOI：
10.1158/0008-5472.can-08-0029
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Drucker, Daniel J.
中科院分区：
文献类型：
--
作者：
Koehler, Jacqueline A.;Harper, Will;Drucker, Daniel J.
胰高血糖素样肽-2 （GLP-2）由肠内分泌细胞分泌，对正常和损伤的肠上皮具有促进吸收、再生和细胞保护作用。因此，持续的GLP-2受体（GLP-2R）激活代表了一种正在研究的预防和治疗化疗诱导的粘膜炎的策略。然而，GLP-2R信号增加对肠道肿瘤细胞生长和存活的影响仍然知之甚少。我们研究了GLP-2在稳定转染GLP-2R的人结肠癌细胞和携带GLP-2R（+）人结肠癌细胞的裸鼠中的增殖和细胞保护作用。在长期外源性GLP-2治疗的Apc（Min/+）小鼠和Apc(Min/+): GLP-2R（-/-）小鼠中也检测了GLP-2R对肿瘤生长的重要性。GLP-2增加了循环AMP的积累，并在DLD-1、SW480和HT29细胞中产生细胞特异性的生长和存活途径激活。然而，GLP-2在体外不刺激细胞生长或减弱环己亚胺-、LY294002-、吲哚美辛-或化疗诱导的细胞毒性。此外，长期给药GLP-2对裸鼠体内人结肠癌细胞异种移植物的生长没有影响。在Apc（Min/+）小鼠中，每天GLP-2治疗7周后，正常肠道黏膜的生长增加，但息肉的数量和大小没有增加，而Apc（Min/+）小鼠中Glp2r基因的遗传破坏也没有改变息肉的大小和数量。综上所述，尽管GLP-2R激活参与了促进正常肠道上皮细胞增殖和细胞保护的信号通路，但GLP-2R信号的持续直接或间接调节并不会改变肠道肿瘤细胞的生长或存活。
Glucagon-like peptide-2 (GLP-2) secreted from enteroendocrine cells exerts proabsorptive, regenerative, and cytoprotective actions in the normal and injured gut epithelium. Hence, sustained GLP-2 receptor (GLP-2R) activation represents a strategy under investigation for the prevention and treatment of chemotherapy-induced mucositis. Nevertheless, the consequences of increased GLP-2R signaling for the growth and survival of intestinal tumor cells remain poorly understood. We studied the proliferative and cytoprotective actions of GLP-2 in human colon cancer cells stably transfected with the GLP-2R and in nude mice harboring GLP-2R(+) human colon cancer cells. The importance of the GLP-2R for tumor growth was also examined in Apc(Min/+), mice chronically treated with exogenous GLP-2 and in Apc(Min/+):Glp2r(-/-) mice. GLP-2 increased cyclic AMP accumulation and produced cell-specific activation of growth and survival pathways in DLD-1, SW480, and HT29 cells. However, GLP-2 did not stimulate cell growth or attenuate cycloheximide-, LY294002-, indomethacin-, or chemotherapy-induced cytotoxicity in vitro. Moreover, chronic GLP-2 administration had no effect on the growth of human colon cancer cell xenografts in nude mice in vivo. Daily GLP-2 treatment for 7 weeks increased growth of normal gut mucosa but did not increase the number or size of polyps in Apc(Min/+) mice, and genetic disruption of the Glp2r gene in Apc(Min/+) mice did not modify polyp size or number. Taken together, although GLP-2R activation engages signaling pathways promoting cell proliferation and cytoprotection in the normal gut epithelium, sustained direct or indirect modulation of GLP-2R signaling does not modify intestinal tumor cell growth or survival.