Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in glioblastoma.

PURPOSE: Glioblastoma (GBM) is one of the most aggressive and incurable primary brain tumors. Identification of novel therapeutic targets is an urgent priority. Programmed cell death 10 (PDCD10), a ubiquitously expressed apoptotic protein, has shown a dual function in different types of cancers and in chemo-resistance. Recently, we reported that PDCD10 was downregulated in human GBM. The aim of this study was to explore the function of PDCD10 in GBM cells. METHODS: PDCD10 was knocked down in three GBM cell lines (U87, T98g and LN229) by lentiviral-mediated shRNA transduction. U87 and T98g transduced cells were used for phenotype study and LN229 and T98g cells were used for apoptosis study. The role of PDCD10 in apoptosis and chemo-resistance was investigated after treatment with staurosporine and temozolomide. A GBM xenograft mouse model was used to confirm the function of PDCD10 in vivo. A protein array was performed in PDCD10-knockdown and control GBM cells. RESULTS: Knockdown of PDCD10 in GBM cells promoted cell proliferation, adhesion, migration, invasion, and inhibited apoptosis and caspase-3 activation. PDCD10-knockdown accelerated tumor growth and increased tumor mass by 2.1-fold and led to a chemo-resistance of mice treated with temozolomide. Immunostaining revealed extensive Ki67-positive cells and less activation of caspase-3 in PDCD10-knockdown tumors. The protein array demonstrated an increased release of multiple growth factors from PDCD10-knockdown GBM cells. CONCLUSIONS: Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in GBM, suggesting PDCD10 as a potential target for GBM therapy.

Comparison of cardiac stem cells and mesenchymal stem cells transplantation on the cardiac electrophysiology in rats with myocardial infarction.

INTRODUCTION: Whether transplanted cardiac stem cells (CSCs) and mesenchymal stem cells (MSCs) improved ventricular fibrillation threshold (VFT) similarly is still unclear. We sought to compare the effects of the CSC and MSC transplantation on the electrophysiological characteristics and VFT in rats with myocardial infarction (MI). METHODS: MI was induced in 30 male Sprague-Dawley rats. Two weeks later, animals were randomized to receive 5 × 10(6) CSCs labeled with PKH26 in PBS or 5 × 10(6) MSCs labeled with PKH26 in phosphate buffer solution(PBS) or PBS alone injection into the infarcted anterior ventricular free wall. Six weeks after the injection, electrophysiological characteristics and VFT were measured. Labeled CSCs and MSCs were observed in 5 µm cryostat sections from each heart. RESULTS: Malignant ventricular arrhythmias were significantly (P = 0.0055) less inducible in the CSC group than the MSC group. The VFTs were improved in the CSC group compared with the MSC group. Labeled CSCs and MSCs were identified in the infarct zone and infarct marginal zone. Labeled CSCs expressed Connexin-43, von Willebrand factor, α-smooth muscle actin and α-sarcomeric actin,while the Labeled MSCs expressed von Willebrand factor, α-smooth muscle actin and α-sarcomeric actin in vivo. CONCLUSIONS: After 6 weeks of cell transplantation, CSCs are superior to MSCs in modulating the electrophysiological abnormality and improving the VFT in rats with MI. CSCs and MSCs express markers that suggest muscle, endothelium and vascular smooth muscle phenotypes in vivo, but MSCs rarely express Connexin-43.