紫檀芪經由降低血生性的Lewis Lung Carcinoma Cells表面多聚體纖連蛋白的組裝抑制肺臟轉移

Abstract

Lung cancer is currently the most prevalent malignant tumor worldwide and has the fastest rising incidence and mortality rate of any cancer. The major problem for cancer patients is metastasis. The metastatic spread of cancer causes 90 % of human cancer deaths. Therefore, interfering metastasis may become the urgent subject. However, in the present, most of the cancer therapy used cytotoxic drugs, which induced severe side effects of cancer patients. Hence, using the lower doses of drugs, which also effectively inhibit metastasis may decrease side effects and prolong the lifespan of cancer patients. It has been suggested for a long time that tumor cells metastasize to its target organs with preferences, which is further supported that cancer cell selectively metastasize through the molecular on the surface of cancer cells interaction with their target organ. Fibronectin (FN) is a multifunctional glycoprotein. Recently, some researches supported that it is related with the polymeric fibronectin (polyFN) assembly on the surface of cancer cells and pulmonary metastasis. In this study, we first found the effect of pterostilbene in inhibiting polyFN was the most effective among four hydroxystilbenes. Pterostilbene was first isolated from P. santa-linus (red sandalwood), and has been shown diverse pharmacologic activities including antioxidant, anti-inflammation, anti-cancer, anti-metastasis and hypolipidemic activates. However, the effects of pterostilbene in anti-metastasis of lung cancer have not been studied. The aim of this study is to estimate the effects of pterostilbene in inhibiting pulmonary metastasis via suppressing polyFN assembly on the surface of blood-borne Lewis Lung Carcinoma（LLC）cells. In the In-vitro study, LLC cells was used and treated with pterostilbene in the end-over-end （EoE）suspension culture. Immunofluorescent staining was used to determine the polyFN assembly on the surface of LLC cells. Cell migration and invasion were determined by Wound-healing assay, Transwell migration assay and Matrigel invasion assay. The expression of proteins that related to polyFN assembly mechanisms were analyzed by Western blotting. In the In-vivo study, Lewis Lung Carcinoma-bearing Mouse Model in C57BL/6 mice was used to evaluate the possible anti-metastasis effects of pterostilbene. The results showed that FN knockdown inhibited LLC cells pulmonary metastasis in C57BL/6 mice. Pterostilbene did not reduce cell viability but significantly inhibited polyFN expression on the surface of suspended LLC cells（treated with pterostilbene under 100 μM for 4hrs）. Pterostilbene inhibited polyFN assembly through increasing Akt and decreasing ERK activity. In addition, pterostilbene treated LLC cells with lower polyFN assembly were injected into the lateral tail vein of C57BL/6 mice, and the results showed that pulmonary metastasis was significantly inhibited when compared with control group. Taken together, our study indicated that pterostilbene could be a promising agent in inhibiting lung metastasis through inhibition of polyFN assembly.