BACKGROUND: Beta-catenin has been implicated in cell-cell communication in a wide variety of developmental and physiological processes. Defective Wnt signaling could result in various cardiac and vascular abnormalities. Little is known regarding Wnt/frizzled pathway in cardiomyocyte apoptosis.
METHODS: In this study, the role of b-catenin in apoptosis was investigated in H9c2 cardiomyocytes and primary cardiomyocytes isolated in diabetic Wistar rats. The cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-b-catenin plasmid in order to overexpress b-catenin.
RESULTS: The transcription factor displayed a significant nuclear localization in Wistar rats with cardiac hypertension. Transfection of b-catenin plasmid induced apoptosis and reduced expression of survival pathway markers in cardiomyocytes in a dose-dependent manner. Furthermore, expression of fibrosis protein markers was upregulated by the overexpression.
CONCLUSIONS: Taken together, these results revealed that altered Wnt/b-catenin signaling might provoke heart failure. (Cardiol J 2017; 24, 2: 195-205).

Activation of apoptosis in cardiomyocytes by saturated palmitic acids contributes to cardiac dysfunction in diabetic cardiomyopathy. Beta-catenin (b-catenin) is a transcriptional regulator of several genes involved in survival/anti-apoptosis. However, its role in palmitate-induced cardiomyocyte apoptosis remains unclear. Glucagon-like peptide 1 (GLP1) has been shown to exhibit potential cardioprotective properties. This study was designed to evaluate the role of b-catenin signalling in palmitate-induced cardiomyocyte apoptosis and the molecular mechanism underlying the protective effects of GLP1 on palmitate-stressed cardiomyocytes. Exposure of neonatal rat cardiomyocytes to palmitate increased the fatty acid transporter CD36-mediated intracellular lipid accumulation and cardiomyocyte apoptosis, decreased accumulation and nuclear translocation of active b-catenin, and reduced expression of b-catenin target protein survivin and BCL2. These detrimental effects of palmitate were significantly attenuated by GLP1 co-treatment. However, the anti-apoptotic effects of GLP1 were markedly abolished when b-catenin was silenced with a specific short hairpin RNA. Furthermore, analysis of the upstream molecules and mechanisms responsible for GLP1-associated cardiac protection revealed that GLP1 restored the decreased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3b (GSK3b) in palmitate-stimulated cardiomyocytes. In contrast, inhibition of Akt with an Akt-specific inhibitor MK2206 or blockade of GLP1 receptor (GLP1R) with a competitive antagonist exendin-(9-39) significantly abrogated the GLP1-mediated activation of GSK3b/b-catenin signalling, leading to increased apoptosis in palmitate-stressed cardiomyocytes. Collectively, our results demonstrated for the first time that the attenuated b-catenin signalling may contribute to palmitate-induced cardiomyocyte apoptosis, while GLP1 can protect cardiomyocytes from palmitate-induced apoptosis through activation of GLP1R/Akt/GSK3b-mediated b-catenin signalling.

Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.