title: Low fucose containing bacterial polysaccharide facilitate mitochondria-dependent ROS-induced apoptosis of human lung epithelial carcinoma via controlled regulation of MAPKs-mediated Nrf2/Keap1 homeostasis signaling.
abstract: Reactive oxygen species (ROS), the key mediators of cellular oxidative stress and redox dysregulation involved in cancer initiation and progression, have recently emerged as promising targets for anticancer drug discovery. Continuous free radical assault upsets homeostasis in cellular redox system and regulates the associated signaling pathways to mediate stress-induced cell death. This study investigates the dose-specific pro-oxidative behavior of a bacterial fucose polysaccharide, which attenuated proliferation of different cancer cells. In the fermentation process, Bacillus megaterium RB-05 [GenBank Accession Number HM371417] was found to biosynthesize a polysaccharide with low-fucose content (4.9%), which conferred the maximum anti-proliferative activity (750 µg/mL) against human lung cancer epithelial cells (A549) during preliminary screening. Structural elucidation and morphological characterization of the duly purified polysaccharide was done using HPLC, GC-MS, (1)H/(13)C NMR, and microscopy. The polysaccharide exhibited concentration- and time-dependent anti-proliferative effects against A549 cells by inducing intracellular ROS level and regulating the mitochondrial membrane-permeability following the apoptotic pathway. This process encompasses activation of caspase-8/9/3/7, increase in the ratio of Bax/Bcl2 ratio, translocation of Bcl2-associated X protein (Bax) and cytochrome c, decrease in expression of anti-apoptotic members of Bcl2 family, and phosphorylation of mitogen activated protein kinases (MAPKs). Apoptosis was attenuated upon pretreatment with specific caspase-inhibitors. Simultaneously, during apoptosis, the ROS-mediated stress as well as activated MAPKs triggered nuclear translocation of transcription factors like nuclear factor (erythroid-derived)-like 2 (Nrf2) and promoted further transcription of downstream cytoprotective genes, which somehow perturbed the chemotherapeutic efficacy of the polysaccharide, although using CuPP, a chemical inhibitor of HO-1, apoptosis increased significantly (P < 0.05).
authors.affiliation: Materials Science Centre, Indian Institute of Technology Kharagpur, Kharagpur, WB, India.|Department of Zoology, Immunology Lab, University of Calcutta, Kolkata, WB, India.
authors.forename: Sougata Roy
authors.initials: SR
authors.lastname: Chowdhury
authors.affiliation: Department of Zoology, Immunology Lab, University of Calcutta, Kolkata, WB, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Department of Zoology, Immunology Lab, University of Calcutta, Kolkata, WB, India.
authors.forename: Subir
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, WB, India.
authors.forename: Ramkrishna
authors.initials: R
authors.lastname: Sen
authors.affiliation: Materials Science Centre, Indian Institute of Technology Kharagpur, Kharagpur, WB, India.
authors.forename: Tridib Kumar
authors.initials: TK
authors.lastname: Sinha
authors.affiliation: Materials Science Centre, Indian Institute of Technology Kharagpur, Kharagpur, WB, India.
authors.forename: Ratan Kumar
authors.initials: RK
authors.lastname: Basak
authors.affiliation: Materials Science Centre, Indian Institute of Technology Kharagpur, Kharagpur, WB, India.
authors.forename: Basudam
authors.initials: B
authors.lastname: Adhikari
authors.affiliation: Department of Zoology, Immunology Lab, University of Calcutta, Kolkata, WB, India.
authors.forename: Arindam
authors.initials: A
authors.lastname: Bhattacharyya
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D005643:Fucose / Q000494:pharmacology; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000378:metabolism*; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011135:Polysaccharides, Bacterial / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011135:Polysaccharides, Bacterial; D017382:Reactive Oxygen Species; D005643:Fucose; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: ROS; apoptosis; cell signaling; fucose polysaccharide; lung carcinoma