p-hydroxycinnamaldehyde and Breast-Neoplasms

2'-Hydroxycinnamaldehyde inhibits breast cancer cell invasion. This study examined whether 2'-hydroxycinnamaldehyde, acting as a Michael acceptor, interferes with the ligand binding of low-density lipoprotein receptor-related protein 1 to mediate breast cancer cell invasion. Low-density lipoprotein receptor-related protein 1, one of the direct molecular targets of 2'-hydroxycinnamaldehyde, is a multifunctional endocytic receptor. Changes in the thiol oxidation status of cell surface receptor proteins may function as a molecular switch, influencing ligand(s) binding. The oxidation status of extracellular cysteine thiol groups in MCF-7 and MDA-MB-231 cells was examined using a fluorescence-activated cell sorter with thiol-specific fluorescent probes; Matrigel invasion and wound-healing assays were performed to determine the effects of 2'-hydroxycinnamaldehyde on in vitro cell migration. The molecular mechanisms by which 2'-hydroxycinnamaldehyde acts were evaluated by transient knockdown using siRNA or inhibition of low-density lipoprotein receptor-related protein 1 by receptor-associated protein treatment. 2'-Hydroxycinnamaldehyde increased α-2-macroglobulin binding to low-density lipoprotein receptor-related protein 1, which was alleviated by pretreatment of cells with N-acetylcystein. 2'-Hydroxycinnamaldehyde decreased the extracellular pepsin concentration significantly in a low-density lipoprotein receptor-related protein 1- and α-2-macroglobulin-dependent manner. The anti-invasive effect of 2'-hydroxycinnamaldehyde was mitigated with receptor-associated protein pretreatment, suggesting that low-density lipoprotein receptor-related protein 1 is essential for the effects of 2'-hydroxycinnamaldehyde. From these data, we suggest that 2'-hydroxycinnamaldehyde increases the cysteine thiol oxidation status of low-density lipoprotein receptor-related protein 1 extracellular domains, which results in α-2-macroglobulin ligand binding stimulation. Therefore, pepsin clearance in a low-density lipoprotein receptor-related protein 1-α-2-macroglobulin-dependent manner might be an important molecular mechanism in 2'-hydroxycinnamaldehyde exerting its anti-invasive action on breast cancer cells. Furthermore, our data may provide an opportunity to promote the importance of the thiol oxidation status of cell surface receptor proteins for regulating cellular signaling pathways that are important in cancer progression.

Topics: alpha-Macroglobulins; Breast Neoplasms; Cell Movement; Cinnamates; Female; Humans; LDL-Receptor Related Proteins; Ligands; MCF-7 Cells; Neoplasm Invasiveness; Oxidation-Reduction; Pepsin A; Signal Transduction

Since epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and in maintaining cancer stem cell properties, EMT is emerging as a therapeutic target for inhibiting the metastatic progression of cancer cells. 2'-Hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde, have recently been suggested as promising therapeutic candidates for cancer treatment. The purpose of this study is to investigate the anti-metastatic effect of HCA on breast cancer and the molecular mechanisms by which HCA regulates the transcriptional program during EMT. HCA induces epithelial reversion at nanomolar concentrations by suppressing Snail via the nuclear translocalization of GSK-3β, which results in the transcriptional upregulation of E-cadherin. HCA also activates the transcription factor KLF17, which suppresses Id-1, indicating that HCA inhibits EMT by multiple transcriptional programs. Further, HCA treatment significantly inhibits lung metastasis in a mouse orthotopic breast cancer model. This study demonstrates the anti-metastatic effect of the non-toxic natural compound HCA through attenuation of EMT in a breast cancer model.

Topics: Acrolein; Animals; Antineoplastic Agents; Benzoates; Breast Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Cell Survival; Cinnamates; Disease Models, Animal; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Differentiation Protein 1; MCF-7 Cells; Mice; Neoplasm Metastasis; Snail Family Transcription Factors; Transcription Factors; Transcriptional Activation; Wnt Signaling Pathway