Abstract
Renal cell carcinoma (RCC) is known as one of the most lethal malignancies in the urological system because of its high incidence of metastasis. Tetrandrine (Tet), a traditional Chinese herbal medicine, exerts a potent anti-cancer effect in a variety of cancer cells. However, the anti-metastatic effect of Tet and its possible mechanism in RCC is still unclear. The present study revealed that Tet significantly suppressed the migration and invasion of RCC 786-O and 769-P cells in vitro. Mechanistically, the protein levels of matrix metalloproteinases 9 (MMP-9), phosphorylated PI3K, PDK1, Akt and NF-κB were markedly reduced after Tet treatment. Moreover, co-treatment with LY294002 (PI3K inhibitor) could further enhance the Tet-inhibited migration and invasion, and the NF-κB and MMP-9 protein levels were further decreased. Similar results were observed after PDTC (NF-κB inhibitor) co-treatment. Conversely, SC79, an Akt activator, could partially reverse the anti-metastatic effects of Tet, accompanied by the restoration of NF-κB and MMP-9 protein levels. In conclusion, the current results indicated that Tet inhibited migration and invasion of RCC partially by regulating Akt/NF-κB/MMP-9 signaling pathway, suggesting that Tet may be a potential therapeutic candidate against metastatic RCC.
Highlights
Renal cell carcinoma (RCC) is the third most common urologic malignancy, accounting for approximately 3% of all cancers and 90% of kidney cancers in adults [1]
Similar effects were exhibited in 769-P cells (Fig 1E).The results indicated that Tet markedly inhibited cell growth at the concentration of !0.5 μM in these two cell lines, while Tet at 0.5 μM represented for a less than 10% inhibitory rate of cell proliferation
Our results revealed that co-treatment with LY294002 could further reinforce the anti-metastatic effects of Tet in 786-O and 769-P cells (Fig 4A and 4B), as well as the protein levels of NF-κB and matrix metalloproteinases 9 (MMP-9) compared with the Tet alone and LY294002 alone treatment cells (Fig 4C and 4D)
Summary
Renal cell carcinoma (RCC) is the third most common urologic malignancy, accounting for approximately 3% of all cancers and 90% of kidney cancers in adults [1]. The advanced diagnostic methods and systemic treatment (chemotherapy and radiotherapy), benefits a remarkable improvement in 5-year survival and recurrence-free survival. 30% patients with RCC continue to progress into the metastatic disease, resulting in a median overall survival of metastatic RCC of only 12 months [2]. It is insensitive to chemotherapy, and drugs for immunotherapy and targeted therapy have a low effect on the treatment for metastatic RCC [3]. There is an urgent need to explore novel therapeutic agents against metastatic RCC.
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