title: Cross-talk between endoplasmic reticulum (ER) stress and the MEK/ERK pathway potentiates apoptosis in human triple negative breast carcinoma cells: role of a dihydropyrimidone, nifetepimine.
abstract: Triple negative breast cancers (TNBC) are among the most aggressive and therapy-resistant breast tumors and currently possess almost no molecular targets for therapeutic options in this horizon. In the present study we discerned the molecular mechanisms of potential interaction between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway in inducing apoptosis in TNBC cells. Here we observed that induction of ER stress alone was not sufficient to trigger significant apoptosis but simultaneous inhibition of the MEK/ERK pathway enhanced ER stress-induced apoptosis via a caspase-dependent mechanism. Our study also demonstrated nifetepimine, a dihydropyrimidone derivative as a potent anti-cancer agent in TNBC cells. Nifetepimine down-regulated the MEK/ERK pathway in MDAMB-231 and MDAMB-468 cells and resulted in blockage of ER stress-mediated GRP78 up-regulation. Detailed mechanistic studies also revealed that nifetepimine by down-regulating pERK expression also declined the promoter binding activity of TFII-I to the GRP78 promoter and in turn regulated GRP78 transcription. Studies further extended to in vivo Swiss albino and SCID mice models also revalidated the anti-carcinogenic property of nifetepimine. Thus our findings cumulatively suggest that nifetepimine couples two distinct signaling pathways to induce the apoptotic death cascade in TNBC cells and raises the possibility for the use of nifetepimine as a potent anti-cancer agent with strong immune-restoring properties for therapeutic intervention for this group of cancer bearers.
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054.
authors.forename: Swatilekha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054.
authors.forename: Supriya
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054.
authors.forename: Pushpak
authors.initials: P
authors.lastname: Bhattacharjee
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Mazumder
authors.affiliation: the Department of Chemistry, Maulana Azad College, Kolkata 700013, India, and.
authors.forename: Salil
authors.initials: S
authors.lastname: Putatunda
authors.affiliation: the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India.
authors.forename: Mahadeo
authors.initials: M
authors.lastname: Gorain
authors.affiliation: the Department of Chemistry, Maulana Azad College, Kolkata 700013, India, and.
authors.forename: Arijit
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India.
authors.forename: Gopal C
authors.initials: GC
authors.lastname: Kundu
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, tanya@jcbose.ac.in.
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, parimal@jcbose.ac.in.
authors.forename: Parimal C
authors.initials: PC
authors.lastname: Sen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D011744:Pyrimidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D011744:Pyrimidinones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C576638:ethyl 4-(3-nitro)-phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases
keywords: Apoptosis; Breast Cancer; Caspase; Endoplasmic Reticulum Stress (ER Stress); Extracellular Signal-regulated Kinase (ERK)