Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirus-mediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the co-treatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells.

[Treatment outcome of multidrug resistance related mRNA expression and c-jun-N-terminal kinase activity in patients with acute myeloid leukemia].

BACKGROUND: The multidrug resistance (mdr1), multidrug resistance associated protein (mrp1), and glutathione-s-transferase (gst) pi genes have been associated with treatment failure in acute myeloid leukemia (AML). c-jun N-terminal kinase (JNK) activity is increased in response to chemotherapeutic agent. METHODS: To investigate the significance of multidrug resistance (mdr) parameters and JNK activity, bone marrow or peripheral blood cells from 52 patients with AML were analyzed. RT-PCR was performed for mdr1, mrp1, and gst pi gene expression. JNK expression and activity were measured using an immunoe- nzymatic kinase assay and a western blot method. RESULTS: High level expression of mdr1, mrp1, and gst pi mRNA was observed in 38.5%, 48.1% and 54.3% of AML cases, respectively. The remission rate was significantly low in cases with an older age (>55 yr), a high WBC count, poor chromosomal abnormalities, a high level expression of mdr1 and mrp1. The WBC count and mdr1 mRNA expression were independent predictors for the outcome to induction chemotherapy. There was a shorter duration of overall survival in the patients with an older age, a high WBC count, chromosome aberrations, high level expressions of mdr1 and mrp1 mRNA, and JNK activation. The patient's age, WBC count and chromosomal abnormalities were independent predictors for overall survivals. The majority (28/30) of AML cases did not show any levels of JNK activation except for two cases, which were associated with an extremely high WBC count, chromosomal aberration, high level expressions of mdr1, mrp1 and gst pi mRNA, and treatment resistance. CONCLUSIONS: These data indicate the influences of mdr1 and mrp1 mRNA expression on the clinical outcome of AML to induction chemotherapy. But it will be necessary to investigate further whether blast cells of AML resistant to chemotherapy retain the capacity to activate JNK, and relate to MDR parameters.

Clinicopathological significance of BGP expression in non-small-cell lung carcinoma: relationship with histological type, microvessel density and patients' survival.

AIMS: Brain-type glycogen phosphorylase (BGP) is the major isoform of glycogen phosphorylase found in fetal and neoplastic tissues, and is generally thought to induce glucose supply during an ischaemic period. This study was performed to investigate BGP expression in non-small-cell lung carcinoma (NSCLC). METHODS: A total of 119 cases of NSCLC, including 63 squamous cell carcinomas (SqCCs) and 56 adenocarcinomas (ACs), were imunohistochemically evaluated for BGP expression, and its expression was correlated with clinicopathological parameters. RESULTS: In total, 76.5% were positive, while non-neoplastic bronchial epithelial cells were weakly positive and pneumocytes were negative. High BGP expression was noted in 78.6% of ACs and 36.5% of SqCCs (p=0.001). Microvessel density was higher in the low BGP expression tumours (29.6 +/- 16.9/mm(2)) than in the high expression tumours (22.8+/-13.8/mm(2)) (p=0.017). BGP expression did not correlate with patient age or tumour stage, but was more frequent in females than males. Kaplan-Meier analysis showed that high BGP expression was associated with poorer survival (p=0.032). CONCLUSIONS: BGP is expressed in NSCLC, particularly AC, and is an independent poor prognostic factor.

Differential expression of hypoxia inducible factor-1 alpha and tumor cell proliferation between squamous cell carcinomas and adenocarcinomas among operable non-small cell lung carcinomas.

This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1alpha (HIF-1alpha) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1alpha expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p<0.001), but not with lymph node status, tumor stage, vascular endothelial growth factor expression, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) index (p>0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1alpha positive carcinomas, MVD was significantly higher in HIF-1alpha positive SCCs than in HIF-1alpha positive ACs (p=0.023). The overall survival curves were not associated with HIF-1alpha expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1alpha expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.