Iwaya Chikayo, Nomiyama Takashi, Komatsu Shiho, Kawanami Takako, Tsutsumi Yoko, Hamaguchi Yuriko, Horikawa Tsuyoshi, Yoshinaga Yasuteru, Yamashita Shinichi, Tanaka Tomoko, Terawaki Yuichi, Tanabe Makito, Nabeshima Kazuki, Iwasaki Akinori, Yanase Toshihiko
Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Japan.
Department of General Thoracic, Breast and Pediatric Surgery, School of Medicine, Fukuoka University, Japan.
Endocrinology. 2017 Dec 1;158(12):4218-4232. doi: 10.1210/en.2017-00461.
Incretin therapies have received much attention because of their tissue-protective effects, which extend beyond those associated with glycemic control. Cancer is a primary cause of death in patients who have diabetes mellitus. We previously reported antiprostate cancer effects of the glucagonlike peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4). Breast cancer is one of the most common cancers in female patients who have type 2 diabetes mellitus and obesity. Thus, we examined whether GLP-1 action could attenuate breast cancer. GLP-1R was expressed in human breast cancer tissue and MCF-7, MDA-MB-231, and KPL-1 cell lines. We found that 0.1 to 10 nM Ex-4 significantly decreased the number of breast cancer cells in a dose-dependent manner. Although Ex-4 did not induce apoptosis, it attenuated breast cancer cell proliferation significantly and dose-dependently. However, the dipeptidyl peptidase-4 inhibitor linagliptin did not affect breast cancer cell proliferation. When MCF-7 cells were transplanted into athymic mice, Ex-4 decreased MCF-7 tumor size in vivo. Ki67 immunohistochemistry revealed that breast cancer cell proliferation was significantly reduced in tumors extracted from Ex-4-treated mice. In MCF-7 cells, Ex-4 significantly inhibited nuclear factor κB (NF-κB ) nuclear translocation and target gene expression. Furthermore, Ex-4 decreased both Akt and IκB phosphorylation. These results suggest that GLP-1 could attenuate breast cancer cell proliferation via activation of GLP-1R and subsequent inhibition of NF-κB activation.
由于其组织保护作用，肠促胰岛素疗法受到了广泛关注，这种作用超出了与血糖控制相关的作用。癌症是糖尿病患者的主要死因。我们之前报道了胰高血糖素样肽-1（GLP-1）受体（GLP-1R）激动剂艾塞那肽-4（Ex-4）的抗前列腺癌作用。乳腺癌是2型糖尿病和肥胖女性患者中最常见的癌症之一。因此，我们研究了GLP-1的作用是否能减轻乳腺癌。GLP-1R在人乳腺癌组织以及MCF-7、MDA-MB-231和KPL-1细胞系中表达。我们发现，0.1至10 nM的Ex-4以剂量依赖的方式显著减少了乳腺癌细胞的数量。虽然Ex-4没有诱导细胞凋亡，但它显著且剂量依赖性地减弱了乳腺癌细胞的增殖。然而，二肽基肽酶-4抑制剂利格列汀对乳腺癌细胞增殖没有影响。当将MCF-7细胞移植到无胸腺小鼠体内时，Ex-4在体内减小了MCF-7肿瘤的大小。Ki67免疫组化显示，从Ex-4处理的小鼠中提取的肿瘤中，乳腺癌细胞增殖显著减少。在MCF-7细胞中，Ex-4显著抑制核因子κB（NF-κB）的核转位和靶基因表达。此外，Ex-4降低了Akt和IκB的磷酸化水平。这些结果表明，GLP-1可通过激活GLP-1R并随后抑制NF-κB激活来减轻乳腺癌细胞的增殖。
