title: Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA₂ homologue from Bothrops pauloensis venom.
abstract: This work shows the antitumoral effects of BnSP-6, a Lys 49 PLA2 isolated from Bothrops pauloensis venom, on human breast cancer MDA-MB-231 cells. BnSP-6 caused a dose-dependent cytotoxicity and inhibited cell adhesion. Interestingly, cytotoxic activity of BnSP-6 was significantly lower against MCF10A, a non-tumorigenic breast cell line, suggesting that this PLA2 presented a possible preference for targets in cancer cells. Analysis of cell death on MDA-MB-231 cells showed that BnSP-6 stimulated the autophagy process, as evidenced by labeling of autophagic vacuoles. Moreover, apoptosis assays showed that BnSP-6 induced both early and late apoptosis. Apoptosis of MDA-MB-231 cells was also confirmed by up-regulation of different genes related to the apoptosis pathway, such as TNF, TNFRSF10B, TNFRSF1A and CASP8 and decreased expression of anti-apoptotic genes (BCL2 and BCL2L). In addition, BnSP-6 caused a remarkable increase in gene expression of BRCA2 and TP53 tumor suppressors. Finally, BnSP-6 induced down-regulation of Angiopoetin 1 gene (potent pro-angiogenic factor) and inhibited adhesion and migration of MDA-MB-231 cells suggesting pharmaceutical applications of this PLA2 as an antiangiogenic and anti-metastatic agent. Taken together, our results show that the PLA2 BnSP-6 presents anticancer potential that can be exploited as prototype for the design of new therapies.
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Fernanda Van Petten Vasconcelos
authors.initials: FV
authors.lastname: Azevedo
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Daiana Silva
authors.initials: DS
authors.lastname: Lopes
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Sarah Natalie
authors.initials: SN
authors.lastname: Cirilo Gimenes
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: David Collares
authors.initials: DC
authors.lastname: Achê
authors.affiliation: Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Lara
authors.initials: L
authors.lastname: Vecchi
authors.affiliation: Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Patrícia Terra
authors.initials: PT
authors.lastname: Alves
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Denise de Oliveira
authors.initials: Dde O
authors.lastname: Guimarães
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil; INCT, Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Belo Horizonte, Brazil.
authors.forename: Renata Santos
authors.initials: RS
authors.lastname: Rodrigues
authors.affiliation: Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil.
authors.forename: Luiz Ricardo
authors.initials: LR
authors.lastname: Goulart
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil; INCT, Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Belo Horizonte, Brazil. Electronic address: veridiana@ingeb.ufu.br.
authors.forename: Veridiana de Melo
authors.initials: Vde M
authors.lastname: Rodrigues
authors.affiliation: Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlandia, UFU, Uberlandia, MG, Brazil. Electronic address: kelly@ingeb.ufu.br.
authors.forename: Kelly Aparecida Geraldo
authors.initials: KA
authors.lastname: Yoneyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D017837:Bothrops / Q000378:metabolism*; D001943:Breast Neoplasms; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D003435:Crotalid Venoms / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D006801:Humans; D054467:Phospholipases A2 / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity*; D054730:Protein Interaction Domains and Motifs
chemical_list: D003435:Crotalid Venoms; C479860:BnSP-6; D054467:Phospholipases A2
keywords: Apoptosis; Autophagy; Breast cancer; Cell migration; Phospholipase A(2); Snake venom