Department of Orthopedic and Trauma Surgery, Shandong University, Jinan, China.
Neoplasma. 2013;60(3):240-6. doi: 10.4149/neo_2013_032.
To explore the mechanism about how HMG-CoA reductase (HMGR) inhibitor inhibit proliferation and bone metastases of lung adenocarcinoma in vitro and in vivo.
The HMGR inhibitor simvastatin, human lung cancer cell line A549 and Balb/c nude mouse were used in this study. The mice were randomly divided into 2 groups: control group (0.9% NaCl solution, i.v.) and simvastatin group (5mg/kg simvastatin, i.v.). A scratch assay using A549 cell monolayer was also tested. An invasion assay using collagen-coated membrane in trans-wells was applied to evaluate the effect of simvastatin on the metastatic potential of A549 cells in vitro. The expressions of CD44, PUMA, P53, MMP2 and MMP9 were determined by real-time PCR and western blotting; the phosphorylation status of MAPK/ERK signaling parthway was investigated by western blot. .
Compared with the control group, the migration of A549 cells in simvastatin-treated group was markedly inhibited (p ≤ 0.01). Untreated A549 cells showed marked invasion, while simvastatin significantly inhibited the invasion of tumor cells (p ≤ 0.001). Incubation of A549 cells with simvastatin significantly reduced the levels of CD44, MMP2 and MMP9 (p <0.01), while significantly increased p53 (p < 0.01). Simvastatin significantly inhibits tumor growth and bone metastasis in lung cancer xenograft mouse model, simvastatin can inhibit the kinase phosphorylation inMAPK/ERK signaling parthway.
The HMGR inhibitor simvastatin prevents proliferation and osteolytic bone metastases of lung adenocarcinoma cells in vitro and vivo. Its mechanism may be associated with regulation of CD44, P53, MMP family and inactivation of MAPK/ERK signaling parthway.
探讨 HMG-CoA 还原酶（HMGR）抑制剂在体内外抑制肺腺癌增殖和骨转移的机制。
本研究使用 HMGR 抑制剂辛伐他汀、人肺癌细胞系 A549 和 Balb/c 裸鼠。将小鼠随机分为 2 组：对照组（0.9%NaCl 溶液，iv.）和辛伐他汀组（5mg/kg 辛伐他汀，iv.）。还使用 A549 细胞单层划痕实验进行测试。应用胶原包被膜的 Transwell 侵袭实验评估辛伐他汀对 A549 细胞体外转移潜能的影响。通过实时 PCR 和 Western blot 测定 CD44、PUMA、P53、MMP2 和 MMP9 的表达；通过 Western blot 研究 MAPK/ERK 信号通路的磷酸化状态。
与对照组相比，辛伐他汀处理组的 A549 细胞迁移明显受到抑制（p ≤ 0.01）。未经处理的 A549 细胞表现出明显的侵袭，而辛伐他汀显著抑制肿瘤细胞的侵袭（p ≤ 0.001）。辛伐他汀孵育 A549 细胞显著降低 CD44、MMP2 和 MMP9 的水平（p<0.01），而显著增加 P53 的水平（p<0.01）。辛伐他汀在肺癌异种移植小鼠模型中显著抑制肿瘤生长和骨转移，辛伐他汀可抑制 MAPK/ERK 信号通路的激酶磷酸化。
HMGR 抑制剂辛伐他汀可防止肺腺癌细胞在体内外的增殖和溶骨性骨转移。其机制可能与调节 CD44、P53、MMP 家族和失活 MAPK/ERK 信号通路有关。
