scholarly journals AOP Report: Uncoupling of Oxidative Phosphorylation Leading to Growth Inhibition via Decreased Cell Proliferation

2021 ◽  
Author(s):  
You Song ◽  
Daniel L. Villeneuve
Keyword(s):  
Cell Proliferation ◽  
Oxidative Phosphorylation ◽  
Growth Inhibition ◽  
Uncoupling Of Oxidative Phosphorylation

scholarly journals Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siamak Salehi ◽  
Oliver D. Tavabie ◽  
Augusto Villanueva ◽  
Julie Watson ◽  
David Darling ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Inhibition ◽  
Tumor Aggressiveness ◽  
Novel Treatment ◽  
Tumor Phenotype ◽  
Aggressive Tumor ◽  
In Vivo Growth ◽  
Regulation Of Regeneration

AbstractRegulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

scholarly journals Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

2017 ◽  
Vol 313 (5) ◽  
pp. G524-G536 ◽  
Author(s):  
Sandrina Maertin ◽  
Jason M. Elperin ◽  
Ethan Lotshaw ◽  
Matthias Sendler ◽  
Steven D. Speakman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Oxidative Phosphorylation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Environmental Stresses ◽  
Ductal Adenocarcinoma ◽  
Cell Adaptation ◽  
Autophagy Inhibition ◽  
Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

Role of the Ca2+ cycle in uncoupling of oxidative phosphorylation in liver mitochondria of cold-acclimated rats

1985 ◽  
Vol 82 (3) ◽  
pp. 545-547
Author(s):  
Nicolay N. Brustovetsky ◽  
Evgeni I. Maevsky ◽  
Stella G. Kolaeva ◽  
Lubov S. Danilova ◽  
Nikita G. Solomonov
Keyword(s):  
Oxidative Phosphorylation ◽  
Liver Mitochondria ◽  
Uncoupling Of Oxidative Phosphorylation

Survivin Is Associated With Cell Proliferation and Has a Role in 1a,25-Dihydroxyvitamin D 3 Induced Cell Growth Inhibition in Prostate Cancer

2011 ◽  
Vol 185 (4) ◽  
pp. 1497-1503 ◽  
Author(s):  
Hidekazu Koike ◽  
Yasuyuki Morikawa ◽  
Yoshitaka Sekine ◽  
Hiroshi Matsui ◽  
Yasuhiro Shibata ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Growth Inhibition ◽  
Dihydroxyvitamin D

Structural requirements in the uncoupling of oxidative phosphorylation by N,N′-bis(dichloroacetyl) diamines

1971 ◽  
Vol 20 (7) ◽  
pp. 1393-1403 ◽  
Author(s):  
A.J. Merola ◽  
K.M. Hwang ◽  
M. Jurkowitz ◽  
G.P. Brierley
Keyword(s):  
Oxidative Phosphorylation ◽  
Structural Requirements ◽  
Uncoupling Of Oxidative Phosphorylation

Uncoupling of oxidative phosphorylation

1976 ◽  
Vol 456 (2) ◽  
pp. 129-148 ◽  
Author(s):  
Walter G. Hanstein
Keyword(s):  
Oxidative Phosphorylation ◽  
Uncoupling Of Oxidative Phosphorylation

Partial uncoupling of oxidative phosphorylation induces premature senescence in human fibroblasts and yeast mother cells

2007 ◽  
Vol 43 (6) ◽  
pp. 947-958 ◽  
Author(s):  
Petra Stöckl ◽  
Christina Zankl ◽  
Eveline Hütter ◽  
Hermann Unterluggauer ◽  
Peter Laun ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Human Fibroblasts ◽  
Premature Senescence ◽  
Uncoupling Of Oxidative Phosphorylation ◽  
Mother Cells

scholarly journals Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2

2008 ◽  
Vol 108 (5) ◽  
pp. 979-988 ◽  
Author(s):  
Oszkar Szentirmai ◽  
Cheryl H. Baker ◽  
Szofia S. Bullain ◽  
Ning Lin ◽  
Masaya Takahashi ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Glioblastoma Multiforme ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Treatment Groups ◽  
Endothelial Growth Factor

Object Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Methods Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Results Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. Conclusions These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.

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