title: Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53.
abstract: The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy.
authors: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India.|Graduate Studies, Manipal University, Manipal, Karnataka, 576104, India.
authors: Adeel H
authors: AH
authors: Zaidi
authors: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India.
authors: Nune
authors: N
authors: Raviprakash
authors: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India.|Graduate Studies, Manipal University, Manipal, Karnataka, 576104, India.
authors: Raveendra B
authors: RB
authors: Mokhamatam
authors: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India.|Graduate Studies, Manipal University, Manipal, Karnataka, 576104, India.
authors: Pankaj
authors: P
authors: Gupta
authors: Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India. manna@cdfd.org.in.
authors: Sunil K
authors: SK
authors: Manna
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D001572:Benzofurans / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051304:Profilins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; C495738:PFN1 protein, human; D051304:Profilins; C498143:RELA protein, human; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D014747:Vinblastine; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C105430:benzofuran; D017239:Paclitaxel
keywords: Caspases; Cell death; Chemotherapeutic drugs; NF-κB; Profilin; p53