Tumor Biology

, Volume 36, Issue 2, pp 595–604 | Cite as

Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O

  • Antonio Hernandes Chaves Neto
  • Karin Juliane Pelizzaro-Rocha
  • Maruska Neufert Fernandes
  • Carmen Veríssima Ferreira-Halder
Research Article

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.

Keywords

Riboflavin Irradiated riboflavin Antitumor activity Renal cell carcinoma 

Abbreviations

Bax

Bcl-2 associated x protein

Bcl-2

B-cell CLL/lymphoma 2

PARP-1

Poly(ADP-ribose) polymerase-1

TNFR1

Tumor necrosis factor receptor superfamily, member 1a

TRADD

TNFRSF1A-associated via death domain

TRAF2

TNF receptor-associated factor 2

FasL

Fas ligand (TNF superfamily, member 6)

Fas

Fas (TNF receptor superfamily member 6)

AIF

Apoptosis-inducing factor

c-IAP

Baculoviral IAP repeat containing 2

p53

CG33336 gene product from transcript CG33336-RB

p21

Cyclin-dependent kinase inhibitor 1A

LMWPTP

Low molecular weight phosphotyrosine protein phosphatase

VEGFR-2

Kinase insert domain receptor(a type III receptor tyrosine kinase)

AKT/PKB

Protein serine/threonine kinase B

Src

v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)

MAPK

Mitogen-activated protein kinase

ERK1/2

Extracellular signal-regulated protein kinase 1/2

JNK

Jun-amino-terminal kinase

p38

p38 MAP kinase

VHL

von Hippel–Lindau tumor suppressor

Notes

Acknowledgments

The authors thank the São Paulo Research Foundation – FAPESP (grant 10/50356-8), CNPq (471151/2011-4), and Capes for financial support.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Antonio Hernandes Chaves Neto
    • 1
    • 2
  • Karin Juliane Pelizzaro-Rocha
    • 1
  • Maruska Neufert Fernandes
    • 1
  • Carmen Veríssima Ferreira-Halder
    • 1
  1. 1.Departamento de Bioquímica, Instituto de BiologiaUniversidade Estadual de Campinas (UNICAMP)CampinasBrazil
  2. 2.Departamento de Ciências Básicas, Faculdade de Odontologia de AraçatubaUNESP - Universidade Estadual PaulistaAraçatubaBrazil

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