p-hydroxycinnamaldehyde and Disease-Models--Animal

2'-Hydroxycinnamaldehyde (HCA), the active component isolated from the stem bark of Cinnamomum cassia, exerts anticancer effects through multiple mechanisms. We recently determined that HCA inhibits signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Because STAT3 overactivation has been closely associated with the development of psoriasis, a chronic autoimmune skin disease, we examined whether HCA ameliorates skin lesions in an imiquimod-induced psoriasis-like mouse model. The results showed that intraperitoneal administration of HCA alleviated imiquimod-induced psoriasis-like dermatitis, epidermal thickening, dermal infiltration of inflammatory cells, and proinflammatory cytokine production. Mechanistically, HCA inhibited pyruvate kinase isozyme M2 and STAT3 signaling, leading to the suppression of T cell activation, Th17 cell differentiation, and keratinocyte hyperproliferation. These results suggest that HCA may be a new treatment for psoriasis and other STAT3-mediated skin disorders, such as infection, inflammation and carcinogenesis.

Topics: Animals; Biomarkers; Cell Survival; Cinnamates; Cytokines; Disease Management; Disease Models, Animal; Disease Susceptibility; Imiquimod; Mice; Psoriasis; Pyruvate Kinase; Signal Transduction; STAT3 Transcription Factor; T-Lymphocyte Subsets; Th17 Cells

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