Anagliptin promotes apoptosis in mouse colon carcinoma cells via MCT-4/lactate-mediated intracellular acidosis.
Anagliptin promotes apoptosis in mouse colon carcinoma cells via MCT-4/lactate-mediated intracellular acidosis.
复制标题
阿格列汀通过 MCT-4/乳酸介导的细胞内酸中毒促进小鼠结肠癌细胞凋亡
DOI：
10.3892/etm.2022.11211
复制
发表时间：
2022-04
影响因子：
2.7
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Li Q;Qin X;Kou X;Li J;Li Z;Chen C
癌细胞经常表现出酸性细胞外微环境，其中跨膜pH梯度的反转与肿瘤增殖和转移相关。为了阐明一种新的癌症治疗靶点，本研究旨在确定二肽基肽酶-4抑制剂阿格列汀调节癌症进展期间细胞pH梯度和伴随的细胞外酸中毒的机制。在雄性BALB/c小鼠（体重25-28 g）的右侧皮下注射总计5 × 105个CT-26细胞（重悬于磷酸盐缓冲盐水中）。收获肿瘤样品，并使用乳酸测定试剂盒检测乳酸。免疫组化法检测Ki 67、PCNA。MTT法和流式细胞仪检测细胞活力。用荧光pH指示剂检测细胞内pH值。结果显示，阿格列汀有效地减少了肿瘤生长，但不影响治疗小鼠的体重。阿格列汀可减少肿瘤样本中乳酸盐的蓄积。用阿格列汀处理刺激CT-26细胞的凋亡。在接受阿格列汀治疗后，乳酸排泄抑制伴随着细胞外pH值（pHe）升高。此外，阿格列汀通过单羧酸转运蛋白-4（MCT-4）介导的乳酸排泄诱导细胞内酸化并逆转低pH梯度。此外，阿格列汀通过抑制MCT-4介导的乳酸排泄，逆转异常的跨膜细胞外/细胞内pH梯度，同时降低线粒体膜电位并诱导细胞凋亡。这些数据揭示了anagliptin在调节癌细胞乳酸排泄方面的新功能，表明anagliptin可用作癌症的潜在治疗。
Cancer cells frequently exhibit an acidic extracellular microenvironment, where inversion of the transmembrane pH gradient is associated with tumor proliferation and metastasis. To elucidate a new therapeutic target against cancer, the current study aimed to determine the mechanism by which the dipeptidyl peptidase-4 inhibitor anagliptin regulates the cellular pH gradient and concomitant extracellular acidosis during cancer progression. A total of 5x105 CT-26 cells (resuspended in phosphate buffer saline) were injected subcutaneously in the right flank of male BALB/c mice (weighing 25-28 g). The tumor samples were harvested, and lactate was detected using a lactate assay kit. Immunohistochemistry was used to detect the Ki67 and PCNA. MTT assay and flow cytometric were used to detect cell viability. Intracellular pH was detected by fluorescence pH indicator. The results revealed that anagliptin effectively reduced tumor growth, but did not affect the body weight of treated mice. Anagliptin reduced the accumulation of lactate in tumor sample. Treatment with anagliptin stimulated the apoptosis of CT-26 cells. And lactate excretion inhibition is accompanied by an increase in extracellular pH (pHe) after treatment with anagliptin. Furthermore, anagliptin induced intracellular acidification and reversed the low pHe gradient via monocarboxylate transporter-4 (MCT-4)-mediated lactate excretion. Additionally, anagliptin reversed the aberrant transmembrane extracellular/intracellular pH gradient by suppressing MCT-4-mediated lactate excretion, while also reducing mitochondrial membrane potential and inducing apoptosis. These data revealed a novel function of anagliptin in regulating lactate excretion from cancer cells, suggesting that anagliptin may be used as a potential treatment for cancer.
登录
查看更多内容
影响因子：
--
作者：
De Chiara, Loretta;Paez de la Cadena, Maria;Cordero, Oscar J.
通讯作者：
Cordero, Oscar J.
影响因子：
5.8
作者：
Quade BN;Parker MD;Occhipinti R
通讯作者：
Occhipinti R
影响因子：
4.6
作者：
Pinto LC;Rados DV;Barkan SS;Leitão CB;Gross JL
通讯作者：
Gross JL
影响因子：
6
作者：
Park JH;Pyun WY;Park HW
通讯作者：
Park HW
DOI：
10.1016/j.jcmgh.2018.08.008
发表时间：
2019-01-01
影响因子：
7.2
作者：
Nishina, Sohji;Yamauchi, Akira;Hino, Keisuke
通讯作者：
Hino, Keisuke