血管紧张素转换酶抑制剂赖诺普利通过诱导 MMP2 分泌刺激黑色素瘤细胞侵袭。

The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion.

机构信息

Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.

Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany,

出版信息

Cell Physiol Biochem. 2022 Sep 5;56(5):457-483. doi: 10.33594/000000570.

DOI:10.33594/000000570

PMID:36057984

Abstract

BACKGROUND/AIMS: Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study.

METHODS

Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100.

RESULTS

Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer.

CONCLUSION

Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.

摘要

背景/目的：高血压的主要治疗方法是使用血管紧张素 II（ATII）受体阻滞剂（ARB）和血管紧张素转换酶（ACE）抑制剂（ACEI）。ATII 和 ACEI 均可通过 ACE 触发信号转导，ARB/ACEI 治疗与癌症风险增加之间可能存在关联，这一问题极具争议性。本研究旨在探讨 ARB/ACEI 治疗是否会通过 ACE 作为潜在信号转导器影响人类黑色素瘤（MV3）细胞的行为。

方法

通过 qPCR 检测 MV3 细胞中 ACE、ATII 受体 1 型和 2 型（AT1R、AT2R）、COX2 和 MMP2 的表达。分别使用洛沙坦、EMA401 和赖诺普利抑制 AT1R、AT2R 和 ACE。使用视频显微镜和 Boyden 室分析 MV3 细胞在肝细胞（Huh7）单层或重建的 I 型胶原基质上的黏附、迁移和侵袭。通过测量跨上皮电阻（TEER）来确认 Huh7 细胞层的完整性。通过 Western blot 评估 ERK1/2 磷酸化和 MMP2 分泌。使用 ARP-100 抑制 MMP2 活性。

结果

洛沙坦、EMA401 和赖诺普利在 Huh7 细胞共培养模型中刺激 MV3 黑色素瘤细胞迁移和侵袭，而对增殖和黏附影响不大。这些药物不干扰肝细胞单层的 TEER，也不影响 MV3 细胞的增殖，但倾向于增加 ERK1/2 的磷酸化以及 COX2 和 MMP2 的表达。赖诺普利导致 MV3 细胞 MMP2 分泌显著增加，并加速 MV3 细胞介导的 TEER 破坏。MMP2 抑制剂 ARP-100 可拮抗赖诺普利刺激的肝细胞层侵袭。