Cross-talk between Cellular Stress, Cell Cycle and Anticancer Agents: Mechanistic Aspects

Tiligada, Ekaterini; Miligkos, V.; Delitheos, A.

doi:10.2174/1568011023353976

Cited by 22 publications

(17 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently identified molecular targets for new anticancer agents include, inducers of cell differentiation, cell cycle arrest, and apoptosis, as well as inhibitors of mitogenic signaling pathways elicited by growth factors and cytokines [2], [3], [4]. A largely unexplored opportunity is the use of carbohydrate mimetics as drugs [5].…”

Section: Introductionmentioning

confidence: 99%

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

Basappa¹,

Sugahara

Thimmaiah

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF) pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl)-3H-imidazole-4-carbaldehyde) was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS), which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7) which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor.

show abstract

Section: Introductionmentioning

confidence: 99%

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

Basappa¹,

Sugahara

Thimmaiah

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Cellular responses to stress can progress to apoptosis or adaptive responses (24). Stress induces different responses depending upon its nature, duration, and severity (25).…”

Section: Nde1 and Cs Protected From Denaturation By Rhres Were Enzymamentioning

confidence: 99%

Human resistin, a proinflammatory cytokine, shows chaperone-like activity

Suragani

Pinjari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Resistin, a cysteine-rich adipocytokine, proposed as a link between obesity and diabetes in mice, was shown as a proinflammatory molecule in humans. We earlier reported that human resistin (hRes), a trimer, was resistant to heat and urea denaturation, existed in an oligomeric polydispersed state, and showed a concentrationdependent conformational change. These properties and an intimate correlation of hRes expression with cellular stress prompted us to investigate hRes as a possible chaperone. Here, we show that recombinant human resistin was able to protect the heat-labile enzymes citrate synthase and Nde1 from thermal aggregation and inactivation and was able to refold and restore their enzymatic activities after heat/guanidinium chloride denaturation. Furthermore, recombinant human resistin could bind misfolded proteins only. Molecular dynamics-based association-dissociation kinetics of hRes subunits pointed to resistin being a molecular chaperone. Bis-ANS, which blocks surface hydrophobicity, abrogated the chaperone activity of hRes, establishing the importance of surface hydrophobicity for chaperone activity. Replacement of Phe49 with Tyr (F49YhRes), a critical residue within the hydrophobic patch of hRes, although it could prevent thermal aggregation of citrate synthase and Nde1, was unable to refold and restore their activities. Treatment of U937 cells with tunicamycin/thapsigargin resulted in reduced hRes secretion and concomitant localization in the endoplasmic reticulum. Escherichia coli transformants expressing hRes could be rescued from thermal stress, pointing to hRes's chaperone-like function in vivo. HeLa cells transfected with hRes showed protection from thapsigargin-induced apoptosis. In conclusion, hRes, an inflammatory protein, additionally exhibited chaperone-like properties, suggesting a possible link between inflammation and cellular stress.protein folding | chaperokine R esistin, a small cysteine-rich secreted protein, is predominantly produced in human macrophages (1, 2). Resistin levels in human serum could neither be associated with obesity nor linked with insulin resistance (3), pointing to possible other role(s) for this hormone. We, and later others, showed that human resistin (hRes) is a proinflammatory molecule that stimulates the synthesis and secretion of TNF-α and IL-12 from macrophages through an NF-κB-activated pathway (4, 5). hRes mRNA levels are strongly induced by TNF-α and IL-6 in human peripheral blood mononuclear cells (6, 7). Although human and mouse resistin share 64.4 and 59% sequence homology at mRNA and amino acids levels, respectively, they differ considerably in terms of their structural organization (8). We earlier reported, based on extensive biophysical analyses, that recombinant human resistin (rhRes) is a highly stable molecule that exists in oligomeric states as a function of concentration with no major loss in helicity and displays slightly altered tertiary structure with an increase in temperature (9, 10). The variable oligomeric states and poly-dispersity...

show abstract

“…They may be regarded as inducers of the pharmacological stress response [5] and they can bring about genomic instability and cytotoxicity similarly to other types of stress including acidic pH and oxidative stress [23]. Sensitivity or resistance to anticancer agents involves processes independent of or subsequent to the interaction between the drug and the Similarly, in response to heat stress, several cochaperones of hsp90 elicit a marked redistribution from cytoplasmic and/or organellar to nuclear sites [34].…”

Section: Subcellular Trafficking Of Heat-shock Proteinsmentioning

confidence: 99%

“…malignancy [5]. Moreover, the hypothesis that cancer may be an adaptive response to cellular stress must not be disregarded [6].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Tiligada¹

2006

CMC

Self Cite

View full text Add to dashboard Cite

The function of many endogenous molecules in all eukaryotic cells depends on their subcellular localisation, being active when localized in one cellular compartment and inactive in another. Translocation or re-localization of mislocalized components in the optimal subcellular site may contribute to the development of novel cancer therapies and to the re-evaluation of conventional treatment. For instance, various agents are able to entrap cytoplasmic anti-apoptotic pathways to the nucleus, thus activating apoptosis. Moreover, amongst the factors identified so far, the optimal location of the tumor suppressor p53 for promoting cell arrest and apoptosis seems to be the nucleus, while the nuclear factor kappa B (NFkappaB) is desirable to stay in the cytoplasm. Thus, the mechanisms of nuclear translocation of endogenous signaling components, like p53, NFkappaB and various heat shock proteins (HSPs), may serve as targets for pharmacological intervention, without excluding the possible role of uptake and active transport into the nucleus of extracellular proteins.

show abstract

Cross-talk between Cellular Stress, Cell Cycle and Anticancer Agents: Mechanistic Aspects

Cited by 22 publications

References 0 publications

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

Human resistin, a proinflammatory cytokine, shows chaperone-like activity

Nuclear Translocation During the Cross-Talk Between Cellular Stress, Cell Cycle and Anticancer Agents

Contact Info

Product

Resources

About