Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.
Cofilin is a member of the actin-depolymerizing factor (ADF) family protein, which plays an essential role in regulation of the mitochondrial apoptosis. It remains unclear how cofilin regulates the mitochondrial apoptosis. Here, we report for the first time that natural compound 4-methylthiobutyl isothiocyanate (erucin) found in consumable cruciferous vegetables induces mitochondrial fission and apoptosis in human breast cancer cells through the mitochondrial translocation of cofilin. Importantly, cofilin regulates erucin-induced mitochondrial fission by interacting with dynamin-related protein (Drp1). Knockdown of cofilin or Drp1 markedly reduced erucin-mediated mitochondrial translocation and interaction of cofilin and Drp1, mitochondrial fission, and apoptosis. Only dephosphorylated cofilin (Ser 3) and Drp1 (Ser 637) are translocated to the mitochondria. Cofilin S3E and Drp1 S637D mutants, which mimick the phosphorylated forms, suppressed mitochondrial translocation, fission, and apoptosis. Moreover, both dephosphorylation and mitochondrial translocation of cofilin and Drp1 are dependent on ROCK1 activation. In vivo findings confirmed that erucin-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model is associated with the mitochondrial translocation of cofilin and Drp1, fission and apoptosis. Our study reveals a novel role of cofilin in regulation of mitochondrial fission and suggests erucin as a potential drug for treatment of breast cancer.
Glioma is the most common and malignant form of primary brain tumour, and is characterised by high proliferation and extensive invasion and neurological destruction. Demethylzeylasteral (T-96), which is extracted from Tripterygium wilfordii, is considered to have immunosuppressive, anti-inflammatory and anti-angiogenic effects. Here, the anti-tumour effect of T-96 on glioma was evaluated. Our results demonstrated that T-96 significantly inhibited glioma cell growth and induced cell cycle arrest in G1 phase but did not induce apoptosis. Cell invasion and migration were dramatically suppressed after treatment with T-96. Almost all genes related to cell cycle and DNA replication were downregulated after treatment with T-96. Our results showed that miR-30e-5p was noticeably upregulated after T-96 treatment, and MYBL2, which is involved in cell cycle progression and is a target gene of miR-30e-5p, was significantly reduced in synchrony. Overexpression of MYBL2 partially rescued the T-96-induced inhibition of cell growth and proliferation. Moreover, a miR-30e-5p antagomir significantly reduced the upregulation of miR-30e-5p expression induced by T-96, leading to recovery of MYBL2 expression, and partially rescued the T-96-induced inhibition of cell growth and proliferation. More important, T-96 effectively upregulated miR-30e-5p expression and downregulated MYBL2 expression, thus inhibiting LN-229 cell tumour growth in a mouse model. These results indicated that T-96 might inhibit glioma cell growth by regulating the miR-30e-5p/MYBL2 axis. Our study demonstrated that T-96 might act as a promising agent for malignant glioma therapy.
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