title: Targeting Mortalin by Embelin Causes Activation of Tumor Suppressor p53 and Deactivation of Metastatic Signaling in Human Breast Cancer Cells.
abstract: Embelin, a natural quinone found in the fruits of Embelia ribes, is commonly used in Ayurvedic home medicine for a variety of therapeutic potentials including anti-inflammation, anti-fever, anti-bacteria and anti-cancer. Molecular mechanisms of these activities and cellular targets have not been clarified to-date. We demonstrate that the embelin inhibits mortalin-p53 interactions, and activates p53 protein in tumor cells. We provide bioinformatics, molecular docking and experimental evidence to the binding affinity of embelin with mortalin and p53. Binding of embelin with mortalin/p53 abrogates their complex resulted in nuclear translocation and transcriptional activation function of p53 causing growth arrest in cancer cells. Furthermore, analyses of growth factors and metastatic signaling using antibody membrane array revealed their downregulation in embelin-treated cells. We also found that the embelin causes transcriptional attenuation of mortalin and several other proteins involved in metastatic signaling in cancer cells. Based on these molecular dynamics and experimental data, it is concluded that the anticancer activity of embelin involves targeting of mortalin, activation of p53 and inactivation of metastatic signaling.
authors.affiliation: Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nupur
authors.initials: N
authors.lastname: Nigam
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi, India.
authors.forename: Shashank P
authors.initials: SP
authors.lastname: Katiyar
authors.affiliation: Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Priyanshu
authors.initials: P
authors.lastname: Bhargava
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Pi-Chao
authors.initials: PC
authors.lastname: Wang
authors.affiliation: Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi, India.
authors.forename: Durai
authors.initials: D
authors.lastname: Sundar
authors.affiliation: Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
authors.forename: Sunil C
authors.initials: SC
authors.lastname: Kaul
authors.affiliation: Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
authors.forename: Renu
authors.initials: R
authors.lastname: Wadhwa
mesh_terms: D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D029623:Primulaceae / Q000737:chemistry*; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C080352:mortalin; C010945:embelin