Metformin Mitigates DPP-4 Inhibitor-Induced Breast Cancer Metastasis via Suppression of mTOR Signaling
Metformin Mitigates DPP-4 Inhibitor-Induced Breast Cancer Metastasis via Suppression of mTOR Signaling
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DOI：
10.1158/1541-7786.mcr-20-0115
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发表时间：
2021-01-01
影响因子：
5.2
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Kawakita, Emi;Yang, Fan;Koya, Daisuke
抗糖尿病药物对癌细胞和糖尿病癌症患者的生物学影响尚未完全阐明。我们报道了二肽基肽酶 (DPP)-4 抑制剂通过 CXCL12/CXCR4/mTOR 轴诱导上皮间质转化 (EMT) 来加速乳腺癌转移。二甲双胍已被证明可以抑制 mTOR 信号通路。在这项研究中，我们研究了二甲双胍是否通过抑制 mTOR 信号传导来减轻 DPP-4 抑制剂诱导的乳腺癌转移。在培养的小鼠乳腺癌和人乳腺癌细胞中，二甲双胍通过抑制与 AMPK 激活相关的 mTOR 途径来抑制 DPP-4 抑制剂 KR62436 (KR) 诱导的 EMT 和细胞迁移。对于体内研究，在有或没有 KR 的同种异体移植 4T1 乳腺癌模型小鼠中进行二甲双胍干预。我们还分析了移植 shRNA 介导的 DPP-4 敲低 4T1 细胞的小鼠。二甲双胍治疗可抑制 KR 给药或 DPP-4 敲低产生的 DPP-4 缺陷型 4T1 乳腺肿瘤细胞的肺转移。原发肿瘤的免疫染色表明，在同种异体移植乳腺癌模型中，DPP-4 抑制通过激活 CXCR4 介导的 mTOR/p70S6K 通路，促进 EMT 诱导转录因子 Snail 的表达；二甲双胍废除了这一改变。二甲双胍治疗不会改变血浆或原发肿瘤中 DPP-4 缺陷诱导的 CXCL12 表达。我们的研究结果表明，二甲双胍可以作为抗转移剂，减轻 DPP-4 抑制剂对某些癌症患者的不良影响。 意义：二甲双胍可以通过 mTOR 抑制对抗 DPP-4 抑制剂对乳腺癌转移的不利影响，这表明其潜在的临床意义。
The biological influence of antidiabetic drugs on cancer cells and diabetic cancer patients has not yet been completely elucidated. We reported that a dipeptidyl peptidase (DPP)-4 inhibitor accelerates mammary cancer metastasis by inducing epithelial-mesenchymal transition (EMT) through the CXCL12/CXCR4/mTOR axis. Metformin has been shown to inhibit the mTOR signaling pathway. In this study, we investigated whether metformin mitigates breast cancer metastasis induced by a DPP-4 inhibitor via suppression of mTOR signaling. In cultured mouse mammary and human breast cancer cells, metformin suppressed DPP-4 inhibitor KR62436 (KR)-induced EMT and cell migration via suppression of the mTOR pathway associated with AMPK activation. For the in vivo study, metformin intervention was performed in an allograft 4T1 breast cancer model mouse with or without KR. We also analyzed mice transplanted with shRNA-mediated DPP-4 knockdown 4T1 cells. Treatment with metformin inhibited the lung metastasis of DPP-4-deficient 4T1 mammary tumor cells generated by either KR administration or DPP-4 knockdown. Immunostaining of primary tumors indicated that DPP-4 suppression promoted the expression of EMT-inducing transcription factor Snail through activation of the CXCR4-mediated mTOR/p70S6K pathway in an allograft breast cancer model; metformin abolished this alteration. Metformin treatment did not alter DPP-4-deficiency-induced expression of CXCL12 in either plasma or primary tumors. Our findings suggest that metformin may serve as an antimetastatic agent by mitigating the undesirable effects of DPP-4 inhibitors in patients with certain cancers.Implications: Metformin could combat the detrimental effects of DPP-4 inhibitor on breast cancer metastasis viamTORsuppression, suggesting the potential clinical relevance.