scholarly journals Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma

2019 ◽  
Author(s):  
Salvatore Rizza ◽  
Luca Di Leo ◽  
Sara Mandatori ◽  
Daniela De Zio ◽  
Giuseppe Filomeni
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Common Mechanism ◽  
Mitochondrial Complex ◽  
Selective Degradation ◽  
Liver Cancers ◽  
Tocopheryl Succinate ◽  
Mitochondrial Defects ◽  
Mitochondrial Toxins

AbstractThe denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR), has been reported to control the selective degradation of mitochondria through mitophagy, by modulating the extent of nitric oxide-modified proteins (S-nitrosylation). The accumulation of S-nitrosylated proteins due to GSNOR downregulation is a feature of hepatocellular carcinoma, causing mitochondrial defects that sensitize these tumors to mitochondrial toxins, in particular to mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). However, it is not known if mitophagy defects contribute to GSNOR-deficient cancer cells sensitivity to αTOS, nor if mitophagy inhibition could be used as a common mechanism to sensitize liver cancers to this toxin. Here, we provide evidence that GSNOR-deficient cancer cells show defective mitophagy. Furthermore, we show that αTOS is a mitophagy inducer and that mitophagy defects of GSNOR-deficient liver cancer cells contribute to its toxicity. We finally prove that the inhibition of mitophagy by depletion of Parkin, a pivotal ubiquitin ligase targeting mitochondria for degradation, enhances αTOS toxicity, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.

scholarly journals Opposing Roles of the Fork-head box genes FoxM1 and FoxA2 in Hepatocellular Carcinoma

2018 ◽  
Author(s):  
Vaibhav Chand ◽  
Akshay Pandey ◽  
Dragana Kopanja ◽  
Grace Guzman ◽  
Pradip Raychaudhuri
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Expression Patterns ◽  
Genetic Evidence ◽  
G1 Phase ◽  
Fork Head ◽  
Liver Cancers ◽  
Differentiation Gene ◽  
Pluripotency Genes

ABSTRACTThe fork-head box transcription factor FoxMl is essential for hepatocellular carcinoma (HCC) development and its overexpression coincides with poor prognosis. Here, we show that the mechanisms by which FoxM1 drives HCC progression involve overcoming the inhibitory effects of the liver differentiation gene FoxA2. First, the expression patterns of FoxM1 and FoxA2 in human HCC are opposite. We show that FoxM1 represses expression of FoxA2 in G1 phase, a phase in the cell cycle in which cells can undergo differentiation. Repression of FoxA2 in G1 phase is important, as it is capable of inhibiting expression of the pluripotency genes that are expressed mainly in S/G2 phases. Using a transgenic mouse model for oncogenic Ras-driven HCC, we provide genetic evidence for a repression of FoxA2 by FoxM1. Conversely, FoxA2 inhibits expression of FoxM1, and inhibits FoxM1-induced tumorigenicity of HCC cells. Moreover, expression of FoxA2 in mouse liver expressing activated Ras inhibits FoxM1 expression and inhibits HCC progression. The observations provide strong genetic evidence for an opposing role of FoxM1 and FoxA2 in HCC progression.AUTHOR SUMMARYLiver cancer remains untreatable because it is diagnosed at a stage when the cancer is aggressive and resistant to therapeutics. The mechanism that drives aggressive liver cancer is poorly understood. These cancers are made up of poorly differentiated cancer cells. Interestingly, the FoxM1 gene is overexpressed in the aggressive liver cancers. Although FoxM1 is important for expression of the proliferation genes, it does not explain why it is overexpressed mainly in the undifferentiated cancers. The current study addresses this puzzle. Our previous studies demonstrated that FoxM1 increases expression of the pluripotency genes that are expressed mainly in the stem-like cells. In the current manuscript we show that, in addition to activating the pluripotency genes, FoxM1 inhibits expression of the liver differentiation gene FoxA2. Overexpression of FoxM1 is important for this inhibition function, as it involves the retinoblastoma family of proteins, which are often inactivated in cancer cells, and thus, are of low-abundance. Moreover, the inhibition of FoxA2 is significant because FoxA2 could inhibit expression of the pluripotency genes as well as FoxM1. The observations provide new insights into how FoxM1 drives progression of aggressive liver cancer.

Glycolysis Inhibition as a Strategy for Hepatocellular Carcinoma Treatment?

2018 ◽  
Vol 19 (1) ◽  
pp. 26-40 ◽  
Author(s):  
A.P. Alves ◽  
A.C. Mamede ◽  
M.G. Alves ◽  
P.F. Oliveira ◽  
S.M. Rocha ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Glucose Transporter ◽  
Public Health Problem ◽  
High Morbidity ◽  
Curative Intent ◽  
Malignant Liver Tumor ◽  
Glucose Transporter 1 ◽  
Inhibition Of Glycolysis

Hepatocellular carcinoma (HCC) is the most frequently detected primary malignant liver tumor, representing a worldwide public health problem due to its high morbidity and mortality rates. The HCC is commonly detected in advanced stage, precluding the use of treatments with curative intent. For this reason, it is crucial to find effective therapies for HCC. Cancer cells have a high dependence of glycolysis for ATP production, especially under hypoxic environment. Such dependence provides a reliable possible strategy to specifically target cancer cells based on the inhibition of glycolysis. HCC, such as other cancer types, presents a clinically well-known upregulation of several glycolytic key enzymes and proteins, including glucose transporters particularly glucose transporter 1 (GLUT1). Such enzymes and proteins constitute potential targets for therapy. Indeed, for some of these targets, several inhibitors were already reported, such as 2-Deoxyglucose, Imatinib or Flavonoids. Although the inhibition of glycolysis presents a great potential for an anticancer therapy, the development of glycolytic inhibitors as a new class of anticancer agents needs to be more explored. Herein, we propose to summarize, discuss and present an overview on the different approaches to inhibit the glycolytic metabolism in cancer cells, which may be very effective in the treatment of HCC.

scholarly journals Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Gabriela Carrasco-Torres ◽  
Rafael Baltiérrez-Hoyos ◽  
Erik Andrade-Jorge ◽  
Saúl Villa-Treviño ◽  
José Guadalupe Trujillo-Ferrara ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Maleic Anhydride ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Malignant Tumors ◽  
Combined Treatment ◽  
Current Data ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.

scholarly journals Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1023
Author(s):  
Eirini I. Rigopoulou ◽  
George N. Dalekos
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Liver Diseases ◽  
Treatment Modalities ◽  
Primary Biliary Cholangitis ◽  
Autoimmune Liver Diseases ◽  
Increased Risk ◽  
Liver Cancers ◽  
Medium Risk ◽  
Causes Of Mortality

Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.

scholarly journals Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1727
Author(s):  
Ana Carolina B. Sant’Anna-Silva ◽  
Juan A. Perez-Valencia ◽  
Marco Sciacovelli ◽  
Claude Lalou ◽  
Saharnaz Sarlak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Carbon Metabolism ◽  
Disease Free Survival ◽  
Building Blocks ◽  
Malignant Cells ◽  
Mitochondrial Complex ◽  
Prostate Cancer Cells ◽  
Prostate Cells ◽  
Malignant Prostate

Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.

scholarly journals Correction to: The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

2018 ◽  
Vol 20 (1) ◽  
Author(s):  
Ma’anit Shapira ◽  
Eli Kakiashvili ◽  
Tzur Rosenberg ◽  
Dan D. Hershko
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Breast Cancer Cells ◽  
Mtor Inhibitor

Autophagy in hypoxia protects cancer cells against apoptosis induced by nutrient deprivation through a beclin1-dependent way in hepatocellular carcinoma

2011 ◽  
Vol 112 (11) ◽  
pp. 3406-3420 ◽  
Author(s):  
Jianrui Song ◽  
Xianling Guo ◽  
Xuqin Xie ◽  
Xue Zhao ◽  
Ding Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Nutrient Deprivation

scholarly journals Radiofrequency Ablation of Hepatocellular Carcinoma: A Literature Review

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Yasunori Minami ◽  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Radiofrequency Ablation ◽  
Safety Margin ◽  
Surgical Techniques ◽  
Evidence Base ◽  
Current Status ◽  
Probe Design ◽  
Curative Therapy ◽  
Management Of Complications ◽  
Liver Cancers

Radiofrequency ablation (RFA) of liver cancers can be performed safely using percutaneous, laparoscopic, or open surgical techniques, and much of the impetus for the use of RFA has come from cohort series that have provided an evidence base for this technique. Here, we give an overview of the current status of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), including its physical properties, to assess the characteristics that make this technique applicable in clinical practice. We review the technical development of probe design and summarize current indications and outcomes of reported clinical use. An accurate evaluation of treatment response is very important to secure successful RFA therapy since a sufficient safety margin (at least 0.5 cm) can prevent local tumor recurrences. We also provide a profile of side effects and information on the integration of this technique into the general management of patients with HCC. To minimize complications of RFA, physicians should be familiar with each feature of complication. Appropriate management of complications is essential for successful RFA treatment. Moreover, adjuvant therapy, such as molecular targeted therapies following curative therapy, is expected to further improve survival after RFA.

Establishment of two distinct human hepatocellular carcinoma cell lines from a single nodule showing clonal dedifferentiation of cancer cells

Hepatology ◽  
1993 ◽  
Vol 18 (2) ◽  
pp. 320-327 ◽  
Author(s):  
Hirohisa Yano ◽  
Akihiro Iemura ◽  
Kazunori Fukuda ◽  
Atsushi Mizoguchi ◽  
Makoto Haramaki ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Human Hepatocellular Carcinoma ◽  
Carcinoma Cell Lines ◽  
Human Hepatocellular Carcinoma Cell ◽  
Hepatocellular Carcinoma Cell

scholarly journals Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Related Hepatocellular Carcinoma

2018 ◽  
Vol 12 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Arnolfo Petruzziello
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Sub Saharan Africa ◽  
Liver Cancers ◽  
B Virus

Introduction:Hepatocellular carcinoma (HCC) is one of the most prevalent primary malignant tumors and accounts for about 90% of all primary liver cancers. Its distribution varies greatly according to geographic location and it is more common in middle and low- income countries than in developed ones especially in Eastern Asia and Sub Saharan Africa (70% of all new HCCs worldwide), with incidence rates of over 20 per 100,000 individuals.Explanation:The most important risk factors for HCC are Hepatitis B Virus (HBV) infection, Hepatitis C Virus (HCV) infection, excessive consumption of alcohol and exposition to aflatoxin B1. Its geographic variability and heterogeneity have been widely associated with the different distribution of HBV and HCV infections worldwide.Chronic HBV infection is one of the leading risk factors for HCC globally accounting for at least 50% cases of primary liver tumors worldwide. Generally, while HBV is the main causative agent in the high incidence HCC areas, HCV is the major etiological factor in low incidence HCC areas, like Western Europe and North America.Conclusion:HBV-induced HCC is a complex, stepwise process that includes integration of HBV DNA into host DNA at multiple or single sites. On the contrary, the cancerogenesis mechanism of HCV is not completely known and it still remains controversial as to whether HCV itself plays a direct role in the development of tumorigenic progression.

Sign in / Sign up

Export Citation Format

Share Document