title: A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production.
abstract: In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.
authors.affiliation: Laboratório de Bioquímica e Biofísica- Instituto Butantan, Av. Vital Brazil, 1500-CEP, 05503-900, São Paulo, SP, Brazil.
authors.forename: Durvanei Augusto
authors.initials: DA
authors.lastname: Maria
authors.forename: Jean Gabriel
authors.initials: JG
authors.lastname: de Souza
authors.forename: Katia L P
authors.initials: KL
authors.lastname: Morais
authors.forename: Carolina Maria
authors.initials: CM
authors.lastname: Berra
authors.forename: Hamilton de Campos
authors.initials: Hde C
authors.lastname: Zampolli
authors.forename: Marilene
authors.initials: M
authors.lastname: Demasi
authors.forename: Simone Michaela
authors.initials: SM
authors.lastname: Simons
authors.forename: Renata
authors.initials: R
authors.lastname: de Freitas Saito
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Ana Marisa
authors.initials: AM
authors.lastname: Chudzinski-Tavassi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D060829:Arthropod Proteins; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D065427:Factor Xa Inhibitors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D041681:NIH 3T3 Cells; D009569:Nitric Oxide / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C559369:Amblyomin-X protein, Amblyomma cajennense; D000970:Antineoplastic Agents; D060829:Arthropod Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D065427:Factor Xa Inhibitors; D006360:Heat-Shock Proteins; D061988:Proteasome Inhibitors; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; D051742:Transcription Factor CHOP; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D053148:Caspase 3; D002118:Calcium