title: Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O.
abstract: Riboflavin (vitamin B2) is a precursor for coenzymes involved in energy production, biosynthesis, detoxification, and electron scavenging. Previously, we demonstrated that irradiated riboflavin (IR) has potential antitumoral effects against human leukemia cells (HL60), human prostate cancer cells (PC3), and mouse melanoma cells (B16F10) through a common mechanism that leads to apoptosis. Hence, we here investigated the effect of IR on 786-O cells, a known model cell line for clear cell renal cell carcinoma (CCRCC), which is characterized by high-risk metastasis and chemotherapy resistance. IR also induced cell death in 786-O cells by apoptosis, which was not prevented by antioxidant agents. IR treatment was characterized by downregulation of Fas ligand (TNF superfamily, member 6)/Fas (TNF receptor superfamily member 6) (FasL/Fas) and tumor necrosis factor receptor superfamily, member 1a (TNFR1)/TNFRSF1A-associated via death domain (TRADD)/TNF receptor-associated factor 2 (TRAF) signaling pathways (the extrinsic apoptosis pathway), while the intrinsic apoptotic pathway was upregulated, as observed by an elevated Bcl-2 associated x protein/B-cell CLL/lymphoma 2 (Bax/Bcl-2) ratio, reduced cellular inhibitor of apoptosis 1 (c-IAP1) expression, and increased expression of apoptosis-inducing factor (AIF). The observed cell death was caspase-dependent as proven by caspase 3 activation and poly(ADP-ribose) polymerase-1 (PARP) cleavage. IR-induced cell death was also associated with downregulation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)/protein serine/threonine kinase B/extracellular signal-regulated protein kinase 1/2 (Src/AKT/ERK1/2) pathway and activation of p38 MAP kinase (p38) and Jun-amino-terminal kinase (JNK). Interestingly, IR treatment leads to inhibition of matrix metalloproteinase-2 (MMP-2) activity and reduced expression of renal cancer aggressiveness markers caveolin-1, low molecular weight phosphotyrosine protein phosphatase (LMWPTP), and kinase insert domain receptor (a type III receptor tyrosine kinase) (VEGFR-2). Together, these results show the potential of IR for treating cancer.
authors.affiliation: Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, 13083-970, Brazil, antoniohernandes@foa.unesp.br.
authors.forename: Antonio Hernandes
authors.initials: AH
authors.lastname: Chaves Neto
authors.forename: Karin Juliane
authors.initials: KJ
authors.lastname: Pelizzaro-Rocha
authors.forename: Maruska Neufert
authors.initials: MN
authors.lastname: Fernandes
authors.forename: Carmen Veríssima
authors.initials: CV
authors.lastname: Ferreira-Halder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D012256:Riboflavin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D051033:Apoptosis Inducing Factor; D053222:Fas Ligand Protein; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D012256:Riboflavin