Tubocapsanolide A Inhibits Transforming Growth Factor-β-activating Kinase 1 to Suppress NF-κB-induced CCR7

Abstract

Withanolides are steroidal lactones that were originally isolated from Withania somnifera, one of the most important herbs used as a traditional remedy for several illnesses in Asian countries (1). These compounds are biologically active and have been shown to inhibit the enzymatic activity of cyclooxygenase-2 and suppress inflammation (2). In addition, recent studies demonstrate that withanolides exhibit anti-cancer effect on human lung, colon, and breast cancer cells in vitro and exert immunopotentiating activity in vivo (3, 4). Several potential mechanisms have been implicated in the inhibition of tumorigenesis by withanolides. First, withanolides induce growth arrest and apoptosis in cancer cells (4, 5). Second, withanolides can inhibit angiogenesis by suppressing endothelial cell proliferation (6). Third, withanolides can reduce cancer cell invasion and metastasis (7). These data suggest that withanolides may be developed as a novel class of anti-cancer drugs.Lymph node invasion by cancer cells is an important step for tumor metastasis and is frequently correlated with early recurrence and poor prognosis. However, the underlying mechanism by which cancer cells metastasize into peripheral lymphatic capillaries is poorly defined. Recent studies indicate that the interaction between chemokine CCL21 and its cognate receptor CCR7 may play an important role in this process (8, 9). The hypothesis suggests that lymphatic endothelial cells (LECs) 2 express and release chemotactic factors such as CCL19 and CCL21 to direct cancer cells with high expression of chemokine receptor CCR7 to grow and migrate toward lymphatic capillaries (10 -12). Indeed, many highly metastatic cancer cells express large amount of CCR7 receptor (13,14), and CCR7 expression is associated with lymph node metastasis in breast, lung, gastric, esophageal cancer, and melanoma (15-19). It is possible that inhibition of CCR7 expression or block of CCL21-CCR7 interaction may cause reduction of lymph node invasion and tumor metastasis. However, the control of CCR7 gene transcription in cancer cells is largely unclear, and no natural products have been shown to regulate CCR7 expression.We have isolated a new bioactive withanolide tubocapsanolide A (Tubo A) from Tubocapsicum anomalum (20). Tubo A exhibited cytotoxic activity on various types of human cancer cells (20). In addition, our recent results demonstrated that Tubo A suppressed the transcription of Skp2 oncogene and up-regulated cyclin-dependent kinase inhibitory proteins p27

TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells

“…1), but with varied efficacy. To be noted, TAK1 has been shown to be constitutively activated in highly metastatic MDA-MB-231 breast cancer cells while its activity is very low in non-metastatic MCF-7 cells33. Consistent with these results, we found that NG25 had a relatively stronger inhibitory effect on MDA-MB-231 cells compared with that on MCF-7 cells, suggesting that TAK1 may be a promising therapeutic target, especially for highly aggressive triple negative breast cancers (Fig.…”

Prospero Homeobox 1 Promotes Epithelial–Mesenchymal Transition in Colon Cancer Cells by Inhibiting E-cadherin via miR-9

“…Equal amounts of cellular proteins were subjected to SDS-PAGE separation, transferred to nitrocellulose, and immunoblotting was conducted by using the appropriate antibodies. Immunofluorescence staining was conducted as described previously (17).…”

Metabolomics and Transcriptional Responses in Estrogen Receptor Positive Breast Cancer Cells

“…The PR/pERK/pMSK1 complex is recruited to the MMTV promoter followed by phosphorylation of H3S10 by pMSK, leading to the displacement of the HP1 repressor complex and the subsequent activation of gene transcription in these cells (Vicent et al, 2008;Vicent et al, 2009). In the ER-cells (eg., MDA-MB-231) MSK has been implicated in the migration and invasion of cells to lymphatic endothelial cells in vitro as well as in in vivo mouse xenograft model through the possible NFκB binding to the chemokine receptor CCR7 (Pan et al, 2009). MSK has also been implicated in cancer-related inflammation through COX2 expression.…”