We report on the role of Hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared to matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared to primary mammary tumors in a mouse model of metastatic breast cancer, the Polyoma Middle-T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, Hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF-1α protein allows not only for inhibition of VEGF-regulated angiogenesis, but also inhibition of compensatory pro-angiogenic pathways and recruitment of bone marrow derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion, that can be partly attributed to decreased membrane localization of the 67kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer.
Tamoxifen resistance is a major problem in the treatment of Estrogen Receptor (ER) positive patients. We have previously reported that Hexamethylene bis-acetamide Inducible Protein 1 (HEXIM1) inhibits ERα activity by competing with ERα for binding to cyclin T1, a subunit of Positive Transcription Elongation b (P-TEFb). This results in the inhibition of the phosphorylation of RNA polymerase II (RNAPII) at serine 2 and the inhibition of transcription elongation of ERα target genes. Since HEXIM1 can inhibit ER activity, we examined whether it plays a critical role in the inhibitory effects of tamoxifen on ER. We observed that tamoxifen induced HEXIM1 recruitment to the promoter region of ER target genes and decreased the recruitment of cyclin T1 and serine 2 phosphorylated RNAPII to the coding regions of these genes. Conversely, in cells wherein HEXIM1 expression has been downregulated we observed attenuation of the inhibitory effects of tamoxifen on estrogen-induced cyclin T1 recruitment to coding regions of ER target genes. As a consequence, downregulation of HEXIM1 resulted in the attenuation of the repressive effects of tamoxifen on estrogen-induced gene expression and proliferation. Conferring clinical relevance to our studies is our analysis of human breast cancer tissue samples that indicated association of lower expression of HEXIM1 with tumor recurrence in patients who received tamoxifen. Our studies provide a better understanding of the mechanistic basis for the inhibitory effect of tamoxifen on ER activity and may suggest new therapeutic targets for the treatment of tamoxifen resistant breast cancer.
Cepharanthine (CEP), a medicinal product derived from Hayata, possesses a potent cytotoxicity against several types of cancers. Recently, we have found that CEP could efficiently inhibit the growth of mutated p53 colon cancer cells, which are often resistant to commonly used chemotherapeutic agents. In this study, we evaluated the cytotoxic effect and the underlying mechanisms of CEP on both chemosensitive CaOV-3 and chemoresistant OVCAR-3 ovarian cancer cell lines. The present study demonstrated that CEP significantly inhibited the growth of CaOV-3 and OVCAR-3 cells in a time- and concentration-dependent manner. CEP arrested CaOV-3 and OVCAR-3 cells in the G1 phase and S phase of cell cycle, respectively. Western blot analysis demonstrated that CEP markedly increased the expression of p21 protein and decreased the expression of cyclins A and D proteins in both CaOV-3 and OVCAR-3 cells. Additionally, CEP triggered apoptotic cell death in OVCAR-3 cells. Taken together, the above results suggest that CEP is a promising anticancer drug for ovarian cancer.
Tamoxifen is widely used as the first line drug for estrogen receptor-positive subtype which is expressed in 70% of overall breast cancer patients. However, approximately 50% of these patients develop acquired resistance after 5 years of treatment, which is characterized by tumor recurrence and metastasis. The epithelial mesenchymal transition (EMT) is an important process in breast cancer invasion. Fundamentally, targeting the EMT represents a crucial therapeutic strategy for preventing or treating breast cancer metastasis. Plumbagin (PLB) is a natural naphthoquinone with significant anticancer effects against several types of tumor cells including breast cancer. In this study, we investigated the effect of PLB on human endocrine-resistant breast cancer cell growth, invasion and the possible mechanisms underlying such actions. PLB exhibited potent cytotoxic activity at a micromolar concentration against endocrine-resistant breast cancer cells. Interestingly, a fixed low concentration of PLB and tamoxifen combination resulted in an increase in growth inhibition in endocrine-resistant cells. In addition, PLB also significantly suppressed mesenchymal biomarker expressions that govern the EMT process, resulting in attenuated metastatic capabilities. In conclusion, PLB should be developed as a pharmacological agent for the use as a single treatment or in combination for endocrine-resistant breast cancer. Copyright © 2016 John Wiley & Sons, Ltd.
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