Abstract
Chondrosarcoma is primary bone cancer, with the forceful capacity to cause local invasion and distant metastasis, and has a poor prognosis. Cancer metastasis is a complication of most cancers; it is one of the leading causes of cancer-related death. Rhodomyrtone is a pure compound that has been shown to induce apoptosis and antimetastasis in skin cancer. However, the inhibitory effect of rhodomyrtone on human chondrosarcoma cell metastasis is largely unknown. Effect of rhodomyrtone on cell viability in SW1353 cell was determined by MTT assay. Antimigration, anti-invasion, and antiadhesion were carried out to investigate the antimetastatic potential of rhodomyrtone on SW1353 cells. Gelatin zymography was performed to determine matrix metalloproteinase-2 (MMP-2) and MMP-9 activities. The effect of rhodomyrtone on the underlying mechanisms was performed by Western blot analysis. The results demonstrated that rhodomyrtone reduced cell viability of SW1353 cells at the low concentration (<3 μg/mL); cell viability was >80%. Rhodomyrtone at the subcytotoxic concentrations (0.5, 1.5, and 3 μg/mL) significantly inhibited cell migration, invasion, and adhesion of SW1353 cells in a dose-dependent fashion. Protein expression of integrin αv, integrin β3, and the downstream migratory proteins including focal adhesion kinase (FAK) and the phosphorylation of serine/threonine AKT, Ras, RhoA, Rac1, and Cdc42 were inhibited after treatment with rhodomyrtone. Moreover, we found that rhodomyrtone decreased the protein level of MMP-2 and MMP-9 as well as the enzyme activity in SW1353 cells. Meanwhile, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression was increased in a dose-dependent fashion. Besides, rhodomyrtone dramatically inhibited the expression of growth factor receptor-bound protein-2 (GRB2) and the phosphorylated form of extracellular signal regulation kinase1/2 (ERK1/2) and c-Jun N-terminal kinase1/2 (JNK1/2). These results indicated that rhodomyrtone inhibited SW1353 cell migration, invasion, and metastasis by suppressing integrin αvβ3/FAK/AKT/small Rho GTPases pathway as well as downregulation of MMP-2/9 via ERK and JNK signal inhibition. These findings indicate that rhodomyrtone possessed the antimetastasis activity that may be used for antimetastasis therapy in the future.
Highlights
Chondrosarcoma, a malignant bone cancer, is the most frequent type of primary bone cancer [1]
We investigated whether rhodomyrtone suppressed cell viability in human chondrosarcoma SW1353 cells
We found that rhodomyrtone significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and tissue inhibitors of metalloproteinases (TIMPs)-2 protein expression in a concentration-dependent manner (Figures 5(a) and 5(b)). is is consistent with our previous study which showed that rhodomyrtone reduced A431 cell metastasis by suppressing matrix metalloproteinase-2 (MMP-2)/9 activities and increasing the expression of TIMP-1 and TIMP-2 [43]
Summary
Chondrosarcoma, a malignant bone cancer, is the most frequent type of primary bone cancer [1]. Overexpression of α2β1, αvβ, αvβ, β1, and β1 integrin in human chondrosarcoma is associated with tumor progression, metastasis, and poor prognosis [5, 8, 15, 16]. Small Rho GTPases including RhoA, Rac, and Cdc are well known to regulate cell migration [20], and overexpression of these molecules in human cancer correlates with cancer progression [21]. Ey are highly expressed in various malignant tumors, and activation of these enzymes enables the degradation of ECM by cancer cells allowing their access to the vasculature as well as migration and invasion into the target organ and development of cancer metastasis [31,32,33]. Our recent studies demonstrated that rhodomyrtone induced apoptosis in skin cancer [43] It was reported as antimetastasis of human skin cancer cells [44]. Molecular mechanisms underlying the antimetastasis effect of rhodomyrtone in SW1353 cells were investigated in vitro to determine the potential of rhodomyrtone as a novel chemotherapeutic drug
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