title: NSAIDs may regulate EGR-1-mediated induction of reactive oxygen species and non-steroidal anti-inflammatory drug-induced gene (NAG)-1 to initiate intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer.
abstract: This study aims to investigate the unclear molecular relationship involved in the activation of intrinsic pathway of apoptosis and NSAID-activated gene-1 (NAG-1) induction as a putative target in NSAIDs-mediated chemoprevention of colorectal cancer. Male Sprague-Dawley rats were administered with a colon-specific pro-carcinogen, 1,2-dimethylhydrazine dihydrochloride to achieve the early stages of colorectal cancer. Histopathological examination was performed for the analysis of neoplastic lesions while flow cytometry was performed for the relative quantification of intracellular reactive oxygen species (ROS), differential mitochondrial membrane potential (MMP or ΔΨ(M)), and apoptotic events. Various target biomolecules were analyzed either for their mRNA or protein expression profiles via RT-PCR and quantitative Real-Time PCR, or Western blotting and immunofluorescence, respectively. Enhanced gene as well as protein expression of pro-apoptotic agents was observed with the daily oral administration of two NSAIDs viz. Sulindac (cyclooxygenase (COX)-non-specific) and Celecoxib (a selective COX-2 inhibitor). A significant increase in early growth response-1 (EGR-1) protein expression and nuclear localization in NSAIDs co-administered animals may have positively regulated the expression of NAG-1 with a significant enhancement of intracellular ROS in turn decreasing the ΔΨ(M) to initiate apoptosis. In silico molecular docking analysis also showed that Sulindac and Celecoxib can block the active site pocket of B-cell lymphoma-extra large (Bcl-xL, anti-apoptotic transmembrane mitochondrial protein) which could be a putative mechanism followed by these NSAIDs to overcome anti-apoptotic properties of the molecule. NSAIDs-mediated up-regulation of EGR-1 and thereby NAG-1 along with implication of higher ROS load may positively regulate the intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer.
authors: Department of Biophysics, Panjab University, Chandigarh, India.
authors: Vivek
authors: V
authors: Vaish
authors: Honit
authors: H
authors: Piplani
authors: Chandan
authors: C
authors: Rana
authors: Kim
authors: K
authors: Vaiphei
authors: Sankar Nath
authors: SN
authors: Sanyal
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D003106:Colon / Q000187:drug effects / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013467:Sulindac / Q000737:chemistry / Q000494:pharmacology*; D051020:bcl-X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C494813:Bcl2l1 protein, rat; D052246:Cyclooxygenase 2 Inhibitors; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D051020:bcl-X Protein; D013467:Sulindac; D019813:1,2-Dimethylhydrazine; D000068579:Celecoxib