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Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

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Related in: MedlinePlus

Relation of HNE activation of heat shock and activationof Bag3. Reproduced with permission from ref (83). Copyright 2009. AmericanSociety for Biochemistry and Molecular Biology.
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fig17: Relation of HNE activation of heat shock and activationof Bag3. Reproduced with permission from ref (83). Copyright 2009. AmericanSociety for Biochemistry and Molecular Biology.

Mentions: Bag3 is a member of a family of six differentgenes characterized initially by their ability to bind to membersof the Bcl2 family of antiapoptopic proteins.84 Our analysis indicated that knockdown of BAG3 dramatically reducedthe levels of antiapoptopic proteins, thereby increasing the sensitivityof the cells to HNE challenge.83 Dramaticreductions in the levels of Bcl2 family members were observed followinglipid electrophile treatment, but knockdown of Bag3 reduced theirlevels even in the absence of HNE. Comparison of the sensitivity toHNE of Hsf1 knocked-down cells indicated that the increased sensitivityof the normal cells to Hsf1 knockdown was completely recapitulatedby Bag3 knockdown. This suggested that despite all of the complexityof the heat-shock response induced by HNE, induction of Bag3 is acritical component. Increases in the level of Bag3 following HNE treatmentleads to the formation of complexes between it, Bcl2 family members,and Hsp70 which protects the Bcl2 family members from hydrolysis inthe proteasome (Figure 17). No impact of Bag3levels is observed on the levels of mRNA of the Bcl2 family members.83


Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

Relation of HNE activation of heat shock and activationof Bag3. Reproduced with permission from ref (83). Copyright 2009. AmericanSociety for Biochemistry and Molecular Biology.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375764&req=5

fig17: Relation of HNE activation of heat shock and activationof Bag3. Reproduced with permission from ref (83). Copyright 2009. AmericanSociety for Biochemistry and Molecular Biology.
Mentions: Bag3 is a member of a family of six differentgenes characterized initially by their ability to bind to membersof the Bcl2 family of antiapoptopic proteins.84 Our analysis indicated that knockdown of BAG3 dramatically reducedthe levels of antiapoptopic proteins, thereby increasing the sensitivityof the cells to HNE challenge.83 Dramaticreductions in the levels of Bcl2 family members were observed followinglipid electrophile treatment, but knockdown of Bag3 reduced theirlevels even in the absence of HNE. Comparison of the sensitivity toHNE of Hsf1 knocked-down cells indicated that the increased sensitivityof the normal cells to Hsf1 knockdown was completely recapitulatedby Bag3 knockdown. This suggested that despite all of the complexityof the heat-shock response induced by HNE, induction of Bag3 is acritical component. Increases in the level of Bag3 following HNE treatmentleads to the formation of complexes between it, Bcl2 family members,and Hsp70 which protects the Bcl2 family members from hydrolysis inthe proteasome (Figure 17). No impact of Bag3levels is observed on the levels of mRNA of the Bcl2 family members.83

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

Show MeSH
Related in: MedlinePlus