Abstract
BackgroundApoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer. Now it is clear that some oncogenic mutations disrupt apoptosis, leading to tumour initiation, progression or metastasis. Here, expression of apoptotic genes in context of drug resistance was investigated.MethodsWe examined total of 102 samples from leukemic patients (n = 60) and patients with solid tumours (n = 42). We used RT-PCR to determine the levels of mRNA expression and the in vitro chemoresistance of leukemic cells was evaluated using the MTT assay.ResultsWe found statistically significant increase in mRNA expression of all investigated proteins (p53, BAX, Bcl-2 and Bcl-XL) between the leukemia samples and leukocytes from healthy volunteers. We did not find any significant difference in mRNA levels among the solid tumour samples. Notably, we showed a significant positive correlation in both leukemic and solid tumour patient groups between p53 and BAX mRNA. We found that the highest values for the Bcl-2/BAX ratio were in solid tumours in comparison to leukemic cells or normal leukocytes. Moreover, we assessed the impact of p53 and BAX mRNA levels on the sensitivity of the leukemic cells to selected cytostatics.ConclusionsElevated levels of p53 and BAX mRNA may indicate cellular response to possible changes in genomic DNA integrity associated with malignant transformation. We suggest that the BAX gene is regulated by the p53 protein but the initiation of apoptosis through the transcription activation of BAX is blocked by the high levels of Bcl-2. Given that the apoptosis resistance mechanisms are different among oncological patients as well as stages of identical malignancy cases, personalized and specific combination therapy is proposed to be more effective in clinical application.
Highlights
Apoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer
Expression of Bcl‐2, Bcl‐XL, B cell CLL/ lymphoma 2 (Bcl-2) associated X (BAX) and p53 mRNA in leukemic samples and solid tumours We compared the expression levels of genes coding for apoptotic proteins in different types of malignant cells
Samples were divided into three groups: controls, leukemias and tumours
Summary
Apoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer. Deregulation of apoptosis (programmed cell death) is considered as one of the most important process in. Vazanova et al Cancer Cell Int (2018) 18:33 apoptotic program. It is well known that p53 suppresses tumour formation and renders protection against DNA damage by inducing cell cycle arrest, DNA repair, or apoptosis [5, 6]. Upon activation triggered by signals like hypoxia or radiation induced DNA damage, p53 acts as zinc-containing transcription factor and regulates downstream genes that are involved in DNA repair, cell cycle arrest or apoptosis. P53 is capable of transcriptional repression of Bcl-2 (B-cell CLL/lymphoma 2) in various cancers including hematopoietic malignancies [8, 9]. P53-mediated regulation of the ratio of Bax versus Bcl-2 protein level can influence the fate of a cell in response to stress [10]. P53 is the most frequently mutated gene in human cancer and the frequency of p53 mutations is highly variable depending on the type of cancer [11]
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