How to target apoptosis signaling pathways for the treatment of pediatric cancers

Apoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer

Investigation of survivin gene polymorphism in patients with gastric carcinoma

Objectives: Despite decreasing incidence of gastric cancerin worldwide, it is still a major health problem. Everyyear, 30.000 new gastric cancer cases emerging, and itis the second most common cancer in Turkey. Gastriccancer is a complex multifactorial disease, emerging byinteraction between genetic and environmental factors.Survivin, apoptosis inhibitory protein is over-expressed incancer tissue. In this study, association between Survivin-31G/C polymorphism and gastric carcinoma was investigated.Materials and Methods: 46 gastric carcinoma patientswho had been admitted at Düzce University Researchand Practice Hospital, Laboratory of Pathology and 42healthy individuals have been included in the study. Sampleshave been subjected to genetic analysis by PCRRFLPmethod in Medical Genetics Department laboratoryat Düzce University.Results: GG genotype was found in 16 (34.8%), GCgenotype in 21 (45.7%), CC genotype in 9 (19.6%) in patientgroup. In control group, genotype distribution werefound 13 (31%), 26 (61.9%) and 3 (7.1%) respectively.The statistically significant difference was not found whencompared between patient and control groups. However,we observed the increased occurrence of gastric cancerassociated with CC genotype (OR=1.52).Conclusions: In our knowledge, this study is the first toevaluate the relationship between gastric carcinoma andSurvivin -31G/C polymorphism in Turkish population. Ourresults show that there is no any association betweengastric carcinoma and Survivin -31G/C polymorphismin the community which is represented by our study andcontrol groups. However, it was concluded that CC genotypemay create the susceptibility to gastric cancer.Key words: Polymorphism, gastric carcinoma, survivinggene, apoptosi

BIRC8 (baculoviral IAP repeat containing 8)

BIRC8, also known as ILP-2, is a homologous protein of BIRC4, however, its function has seldom been addressed. Despite the similarity with other Inhibitory Apoptosis Proteins (IAPs), there is evidence that BIRC8 acts in a peculiar manner, by impeding apoptosis induced by BAX without directly inhibiting the activity of caspases. BIRC8 expression has been detected in testis and lymphoblastic normal cells and, furthermore, it has been reported in different cancers, including breast carcinoma, hematological neoplasms, hepatocellular carcinoma, nasopharyngeal carcinoma, and neuroblastoma. However, the specific implications of such protein for treatment and prognosis must be further evaluated. In this review, current data on RNA, DNA, protein and the association of BIRC8 in cancer are presented

High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer

The aim of our study was to examine the relationship between tumour IKKα expression and breast cancer recurrence and survival. Immunohistochemistry was employed in a discovery and a validation tissue microarray to assess the association of tumour IKKα expression and clinico-pathological characteristics. After siRNA-mediated silencing of IKKα, cell viability and apoptosis were assessed in MCF7 and MDA-MB-231 breast cancer cells. In both the discovery and validation cohorts, associations observed between IKKα and clinical outcome measures were potentiated in oestrogen receptor (ER) positive Luminal A tumours. In the discovery cohort, cytoplasmic IKKα was associated with disease-free survival (p = 0.029) and recurrence-free survival on tamoxifen (p < 0.001) in Luminal A tumours. Nuclear IKKα and a combination of cytoplasmic and nuclear IKKα (total tumour cell IKKα) were associated with cancer-specific survival (p = 0.012 and p = 0.007, respectively) and recurrence-free survival on tamoxifen (p = 0.013 and p < 0.001, respectively) in Luminal A tumours. In the validation cohort, cytoplasmic IKKα was associated with cancer-specific survival (p = 0.023), disease-free survival (p = 0.002) and recurrence-free survival on tamoxifen (p = 0.009) in Luminal A tumours. Parallel experiment with breast cancer cells in vitro demonstrated the non-canonical NF-κB pathway was inducible by exposure to lymphotoxin in ER-positive MCF7 cells and not in ER-negative MDA-MB-231 cells. Reduction in IKKα expression by siRNA transfection increased levels of apoptosis and reduced cell viability in MCF7 but not in MDA-MB-231 cells. IKKα is an important determinant of poor outcome in patients with ER-positive invasive ductal breast cancer and thus may represent a potential therapeutic target

IAPs on the move : role of inhibitors of apoptosis proteins in cell migration

Inhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases. IAPs directly control Rho GTPases, thus regulating cell shape and migration. For instance, XIAP and cIAP1 function as the direct E3 ubiquitin ligases of Rac1 and target it for proteasomal degradation. IAPs are differentially expressed in tumor cells and have been targeted by several cancer therapeutic drugs that are currently in clinical trials. Here, we summarize the current knowledge on the role of IAPs in the regulation of cell migration and discuss the possible implications of these observations in regulating tumor cell metastases

Influence of perinatal factors on gene expression of IAPs family and main factors of pluripotency: OCT4 and SOX2 in human breast milk stem cells : a preliminary report

Due to their therapeutic potential, mesenchymal stem cells are the subject of intensive research on the use of their potential in the treatment of, among others, neurodegenerative diseases or immunological diseases. They are among the newest in the field of medicine. The presented study aimed to evaluate the expression of eight genes from the IAP family and the gene regulating IAP—XAF1—in stem cells derived from human milk, using the qPCR method. The relationships between the expression of genes under study and clinical data, such as maternal age, maternal BMI, week of pregnancy in which the delivery took place, bodyweight of the newborn, the number of pregnancies and deliveries, and the time elapsed since delivery, were also analyzed. The research was carried out on samples of human milk collected from 42 patients hospitalized in The Clinic of Obstetrics and Perinatology of the Independent Public Clinical Hospital No. 4, in Lublin. The conducted research confirmed the expression of the following genes in the tested material: NAIP, BIRC2, BIRC3, BIRC5, BIRC6, BIRC8, XIAP, XAF1, OCT4 and SOX2. Moreover, several dependencies of the expression of individual genes on the maternal BMI (BIRC5, XAF1 and NAIP), the time since childbirth (BIRC5, BIRC6, XAF1 and NAIP), the number of pregnancies and deliveries (BIRC2, BIRC5, BIRC6 and XAF1), the manner of delivery (XAF1 and OCT4), preterm labor (BIRC6 and NAIP) were demonstrated. Additionally, we found positive relationships between gene expression of BIRC7, BIRC8 and XAF1 and the main factors of pluripotency: SOX2 and OCT4. This work is the first to investigate the expression of genes from the IAPs family in mother’s milk stem cells