The Mechanisms of Regulation of Aerobic Glycolysis (Warburg Effect) by Oncoproteins in Carcinogenesis.

According to modern concepts, tumor formation is associated with impairments in the structure of protooncogenes and/or deactivation of suppressor genes, regardless of the nature of carcinogenic factor. As a consequence, unregulated oncoproteins activate extracellular proteases, resulting in the destruction of the extracellular matrix, which facilitates cell invasion, deterioration of the cell-cell contacts, and metastasis. Tumor development requires activation of certain transcription factors; however, many oncoproteins are not transcription factors.

Role of Proton Pumps in Tumorigenesis.

One of the differences between normal and cancer cells is lower pH of the extracellular space in tumors. Low pH in the extracellular space activates proteases and stimulates tumor invasion and metastasis. Tumor cells display higher level of the HIF1α transcription factor that promotes cell switch from mitochondrial respiration to glycolysis.

HYPOXIA AND GLYCOLYSIS AS FACTORS DETERMINING THE MALIGNANT PHENOTYPE.

The review deals with the role of hypoxia and glycolysis in the development of cancer. Experimental results demonstrate that the function of glycolysis in tumour cells is not limited to providing energy. Glycolysis stimulates the activity of transcription factor HIF1a.

[Effect of cell microenvironment on cell functions associated with tumour promotion and progression].

To study the tumour-promotion activity of cell environment the transformed embryonic rat fibroblasts (clone CL-1-1) were transfect to immunodeficient mice then the cells of the formed tumour were cultivated (clone CL-1-1). The cells before and after transplantation were compared by morphology, proliferation activity and gap junction intracellular communications. The clone CL-1 cells proliferated much faster than clone CL-1 cells.

[Inhibitory effect of human lactoferrin (neolactoferrin) on the growth of transplantable tumor in the uterine cervix of mice].

There was studied effect of recombinant form of human breast milk component-lactoferrin, received from milk of goats-producers (neolactoferrin), on growth of transplantable tumor of the cervix in mice (TTC-5). Neolactoferrin in dose of 100 mg/kg and 200 mg/kg of animals' mass inhibited the rate of tumor growth. The most effective was the dose of 200 mg/kg, which was entered a week before transplantation.

[Activation of transcription factor NF-kappaB by carcinogenic polycyclic aromatic hydricarbons].

Effect of carcinogenic polycyclic aromatic hydrocarbons (PAH) benzo(a)pyrene (BP) and 3-methylcholanthrene (MC) on transcription factor NF-kappaB activation was studied. The determination of NF-kappaB activity was performed by two different methods: determination of mRNA expression of NF-kappaB-dependent I-kappaB gene, and determination of transcription activity of co-transfected with the plasmid containing the luciferase reporter gene under the NF-kappaB-sensitive promoter. As a subject of inquiry the hepatoma cell cultures HepG2 expressed Ah receptor and G27 not expressed Ah receptor were used.

Mechanisms of tumor promotion by reactive oxygen species.

This review analyzes the available information concerning mechanisms of non-genotoxic action of reactive oxygen species (ROS) during tumor promotion and pathways of their generation under the influence of chemical compounds. Special attention is given to the ability of ROS to induce pseudohypoxia through inhibition of prolyl oxidase, which is an oxygen sensor in the cell. Functions of HIF-1alpha as a main contributor to the ROS-induced promotion are analyzed.

Appearance of differentiation characteristics (induction of Ah-receptor-dependent genes) during cultivation of transformed cell clone K8 from embryonic rat fibroblasts.

The differentiation status of fibroblasts can be characterized by their ability to induce Ah-receptor-dependent genes. The ability to induce Ah-receptor-dependent genes encoding cytochrome P450 isoforms, Ah-receptor repressor, and NADPH-quinine oxidoreductase were studied in the transformed cell clone K8 obtained from immortalized embryonic rat fibroblasts by treatment with benzo(a)pyrene and in the parental clone F27. Treatment with benz(a)anthracene did not induce the genes in the transformed clone K8 on passages 4-14, but the induction was recorded in the transformed clone beginning from the 16th passage and later, whereas in F27 cells the induction was observed throughout the experiment.

[Ah receptor-independent inhibition of gap junction intercellular communications in hepatoma cell culture 27 by polycyclic aromatic hydrocarbons].

One of the systems that regulate tissue homeostatis is gap junction intercellular communications (GJIC). Inhibition of GJIC is widely used in experiments as a characteristic of tumor promotion. It is accepted that the down-regulation of GJIC is tightly related with the tumor-promoting properties of carcinogens.

Comparative analysis of family 1 cytochrome p-450 mRNA expression in human intestinal adenocarcinoma and intact portion of the intestine.

The expression of mRNA of proteins involved in the transformations of cytostatics (cytochrome P-450 1A1 and 1B1 isoforms) and genes encoding proteins participating in their regulation (Ah receptor, AHRR and ARNT) in intestinal tumors and intact portions of the intestine were studied. The expression of cytochrome P-450 1A1 increased in poorly differentiated tumors in comparison with its expression in intact portions of the intestine (tumor/intact tissue=1.65).

Benzo[a]pyrene-dependent activation of transcription factors NF-kappaB and AP-1 related to tumor promotion in hepatoma cell cultures.

The activation by the carcinogenic polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) of transcription factors NF-kappaB and AP-1 in hepatoma 27 and HepG2 cell cultures was studied. In contrast to the hepatoma HepG2 cells, cytochrome P450 isoforms and Ah-receptor are not expressed in the hepatoma 27 cells. The transcription factor NF-kappaB was activated only in the hepatoma 27 cells by BP treatment but not by its noncarcinogenic isomer benzo[e]pyrene (BeP).

[A comparative study of induction regulation in cytochromes family 1 P450 in cell cultures at different stages of tumor transformation].

Lipophilic xenobiotics, including some carcinogenic agents and cytostatics, are metabolized by cytochrome P450 isoforms (CYP). In tumours expression of CYP genes and their inducibility are lower than in a homologous normal tissue. This phenomenon determines the known higher cytostatic stability of tumour cells.

Expression of mRNA for several enzymes of xenobiotic detoxification in normal and spontaneously transformed mesothelial cells and mesothelioma cells of rats.

Expression of mRNA for the mdr1 gene, cytochrome P450 isoforms 1A1 and 1B1, Ah receptor, and ARNT protein regulating the concentration of cytochrome P450 mRNA was compared in normal and spontaneously transformed mesothelial cells and mesothelioma cells from rats. Expression of cytochrome P450 1A1 and 1B1 mRNA decreased in transformed mesothelial and mesothelioma cells compared to normal mesothelial cells. mRNA for the mdr1 gene was undetected in normal mesothelial cells.

Effect of some carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons on gap junction intercellular communication in hepatoma cell cultures.

One of the systems that regulate tissue homeostasis is gap junction intercellular communication (GJIC). It is accepted that the down-regulation of GJIC is linked to the tumor-promoting properties of carcinogens. In this study, the effect of some carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons (PAH) on GJIC was investigated.

Change in contents of biologically active sphingolipids modulating cell growth and survival in hepatoma 27 compared to rat liver.

The contents of bioactive sphingolipids (sphingomyelin, ceramide, glucosyl- and lactosylceramides, gangliosides) were studied in rat hepatoma 27 and rat liver. The amounts of sphingomyelin, ceramide, and glucosyl- and lactosylceramides were about twofold and that of gangliosides was about 3.5-fold increased in the tumor compared to normal tissue.

Inhibition of gap junction intercellular communications in cell culture by polycyclic aromatic hydrocarbons (PAH) in the absence of PAH metabolism.

We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communications (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non-carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells.

Cytochrome P-450 family 1 in rat embryo cell culture immortalized by Rausher leukemia virus.

We studied comparative expression and activity of cytochrome P450 family 1 (CYP1) isoforms in rat embryo cells, both primary and immortalized by Rausher leukemia virus (RLV). In RLV-infected embryonal cells compared with the initial ones the expression levels of CYP1A1 and 1B1 mRNAs and benzo[a]pyrene (BP) hydroxylase activity were higher, regardless of their treatment with the CYP1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The sensitivity to BP and 7,12-dimethylbenzo[a]anthracene was higher in the cells immortalized with RLV.

[The changes in the sphingenine/sphinganine ratio in sphingolipids of transplantable rat tumors depends on a transplantation organ].

The content of sphingenine (sphingosine) and sphinganine was determined in the total pool of sphingomyelin and ceramide in the rat tumors transplanted subcutaneously and intrahepatically. The sphingenine/sphinganine ratio in the subcutaneously transplanted sarcoma M1 and cholangiocellular carcinoma RS1 was lower than that in the sphingolipids of the intrahepatically transplanted tumors. However, the sphingenine/sphinganine ratio in the subcutaneously transplanted rat hepatoma 27 was higher than in the intrahepatically transplanted hepatoma.

[Effect of some polycyclic aromatic hydrocarbons on gap junction intercellular communication in hepatoma Hep G2 cell culture].

Systems regulating tissue homeostasis are gap junction intercellular communications (GJIC). It is accepted that the down-regulation of GJIP has been due to tumor promoting properties of carcinogens. In this study, effects of some carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons (PAH) on GJIC were investigated.

Comparative study of lipid composition and proliferative activity of rat cholangiocarcinoma RS1 and sarcoma M1 depending on the transplantation organ.

The proliferative activity and lipid composition (phospholipids, gangliosides) were studied in rat cholangiocarcinoma RS1 and sarcoma M1 transplanted subcutaneously or intrahepatically. The mitotic index was higher in the tumors transplanted into the heterologous organ. The total phospholipid and sphingomyelin contents were higher in the tumors transplanted intrahepatically.

Dihydroceramide desaturase activity in tumors.

Dihydroceramide desaturase activity in the transplantable mouse hepatoma-22, rat hepatoma-27, M1 sarcoma, and RS1 rat cholangiocellular carcinoma has been investigated. It was found that the dihydroceramide desaturase activity in mouse hepatoma-22 is lower than that in normal mouse liver. However, the activity of this enzyme in subcutaneously and intrahepatically transplanted rat hepatoma-27 is increased compared to normal value.

[New models of experimental chemotherapy of tumors].

New neoplastic models such as orthotopic solitary hepatic tumor (cholangiocellular cancer PC-1) as well as different strains of malignant pleuritis (hemoblastosis and ascitic tumors) have been evolved by transplanting tumor cell suspension to rat liver or murine pleural cavity. Intrahepatic cancer PC-1 has a solid mucosa-excreting structure and is characterized by low activity of detoxication enzymes of such xenobiotics as glutathione-S-transferase, NAD(p)N-chinonoxyreductase and aldehyde dehydrogenase. Orthotopic hepatic tumor PC-1 may be used for evaluating systemic and regional therapy.

Differences in lipid composition and proliferative activity of rat hepatoma-27 depending on the target organ.

Proliferative activity and lipid composition (phospholipids and gangliosides) were studied in rat hepatoma-27 transplanted subcutaneously or intrahepatically (as models for primary and metastasizing tumors). The mitotic index of subcutaneously transplanted hepatoma far exceeded that of the intrahepatically transplanted tumor. The overall amounts of both phospholipids and gangliosides increased appreciably in the subcutaneously growing hepatoma (in contrast to the intrahepatically growing tumor) in comparison to the control hepatic tissue.

Coordinated regulation of P-glycoprotein activity and cytochrome P-4501A induction in sublines of rat hepatoma McA RH7777 cells with different levels of colchicine resistance.

The constitutive and induced activities of cytochrome P-4501A isoforms in hepatoma McA 7777 sublines with different levels of colchicine (CH) resistance were studied. The higher CH resistance was associated with the elevated functional activity of P-glycoprotein (Pgp). The constitutive level of benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase (cytochrome P-4501A-dependent activities) were the same in sublines with different CH resistance levels.