scholarly journals Gastric tumorigenesis induced either by Helicobacter pylori infection or chronic alcohol consumption through IL-10 inhibition

2020 ◽  
Author(s):  
Faisal Aziz ◽  
Abhijit Chakarobaty ◽  
Kandong Liu ◽  
Hisae Yoshitomi ◽  
Xiang Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alcohol Consumption ◽  
Mitochondrial Dysfunction ◽  
Cell Survival ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Cd8 Cells ◽  
Cancer Cell Survival ◽  
H Pylori

Abstract Background Alcohol is class 1 carcinogen and results in 3.3 million deaths every year. H. pylori is also an important factor for gastric carcinogen. Alcohol consumption is emerging as an important contributor to gastric cancer, but there is no direct or experimental evidence of alcohol and H. pylori infection produce gastric cancer in human and animal model alone. Here, we provide insight into the molecular mechanisms driving gastric carcinogenesis. Results Alcohol consumption, together with H. pylori infection, causes gastric cancer; interleukin-10 (IL-10) downregulation and mitochondrial metabolic dysfunction in CD8+ cells are also involved. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. IL-10 downregulation and CD-8+ cell dysfunction stimulates IL-1β secretion. Specifically, we show IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, In the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this results in mitochondrial dysfunction and production of IL-1 β. IL-1β promotes H. pylori infection and reduces NKX6.3 gene expression, resulting in increased cancer cell survival and proliferation. Conclusions Overall, the molecular mechanisms of gastric carcinogenesis include IL-10 inhibition resulting in lowered host immunity via mitochondrial dysfunction of CD8+ lymphocytes; gastric inflammation due to H. pylori infection, alcohol intake, and IL-1β production; and disruption of gastric-specific tumor suppressor NKX6.3 expression, which increases cancer cell survival and proliferation.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

scholarly journals The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0184514 ◽  
Author(s):  
Pål Vange ◽  
Torunn Bruland ◽  
Berit Doseth ◽  
Reidar Fossmark ◽  
Mirta M. L. Sousa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Rodent Models ◽  
Cancer Cell Survival

scholarly journals Induction and prevention of gastric cancer with combined Helicobacter pylori and capsaicin administration and DFMO treatment, respectively

2020 ◽  
Author(s):  
Faisal Aziz ◽  
Mingxia Xin ◽  
Yunfeng Gao ◽  
Josh Monts ◽  
Kjersten Monson ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Mouse Models ◽  
Chronic Gastritis ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Lifestyle Changes ◽  
Host Susceptibility ◽  
Anti Inflammatory ◽  
H Pylori

Abstract Background: Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes including Helicobacter pylori (H. pylori) infection and consumption of hot peppers (i.e. capsaicin). H. pylori infection promotes gastric mucosal injury in the early phase of capsaicin exposure. In addition, capsaicin consumption is reported to suppress immune function and increase host susceptibility to microbial infection. This relationship suggests a need to investigate the mechanism of how both H. pylori infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. No previous experimental animal models have been developed to study this dual association. Here we developed a series of mouse models that progress from chronic gastritis to gastric cancer. C57-Balb/c mice were infected with the H. pylori (SS1) strain and then fed capsaicin (0.05% or 0.2g/kg/day) or not. Consequently, we investigated the association between H. pylori infection and capsaicin consumption during the initiation of gastric inflammation and the later development of gastric cancer. Tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Gastric carcinogenesis was also prevented in these models using the ornithine decarboxylase inhibitor DFMO (2-difluoromethylornithine). Results: This study provides evidence showing that a combination of H. pylori infection and capsaicin consumption leads to gastric carcinogenesis. The transition from chronic gastritis to gastric cancer is mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. However, this progression can be prevented by treating with anti-inflammatory agents. In particular, we used DFMO to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention. Conclusions: Overall, these mouse models provide reliable systems for analyzing the molecular mechanisms and synergistic effects of H. pylori and capsaicin on human cancer etiology. Accordingly, preventive measures like reduced capsaicin consumption, H. pylori clearance, and DFMO treatment can lessen gastric cancer incidence. Lastly, anti-inflammatory agents like DFMO can play important roles in prevention of inflammation-associated gastric cancer.

scholarly journals New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects

2021 ◽  
Vol 14 (11) ◽  
pp. 1068
Author(s):  
Andrea Arena ◽  
Maria Anele Romeo ◽  
Rossella Benedetti ◽  
Laura Masuelli ◽  
Roberto Bei ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cell ◽  
Cytotoxic Effect ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Cytotoxic Effects ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Anti Oxidant ◽  
Her 2

Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway. Moreover, we found that resveratrol and curcumin in combination exerted a stronger cytotoxic effect in correlation with the induction of a stronger ER stress and the upregulation of pro-death UPR molecule CHOP. This effect also correlated with the induction of pro-survival autophagy by curcumin and its inhibition by resveratrol. In conclusion, this study unveils new molecular mechanisms underlying the anti-cancer effects of resveratrol, curcumin and their combination, which can help to design new therapeutic strategies based on the use of these polyphenols.

Abstract 163: Investigation of molecular mechanisms by which PCA3 modulates prostate cancer cell survival

2015 ◽  
Author(s):  
Ana Emilia Goulart ◽  
Luciana B. Ferreira ◽  
Paula Priscilla de Freitas ◽  
Nadia Batoreu ◽  
MARTIN H. BONAMINO ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Prostate Cancer Cell ◽  
Cancer Cell Survival
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