TY - JOUR

T1 - Recombinant Vaccinia Viruses Coding Transgenes of Apoptosis-Inducing Proteins Enhance Apoptosis but Not Immunogenicity of Infected Tumor Cells

AU - Koval, Olga

AU - Kochneva, Galina

AU - Tkachenko, Anastasiya

AU - Troitskaya, Olga

AU - Sivolobova, Galina

AU - Grazhdantseva, Antonina

AU - Nushtaeva, Anna

AU - Kuligina, Elena

AU - Richter, Vladimir

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Genetic modifications of the oncolytic vaccinia virus (VV) improve selective tumor cell infection and death, as well as activation of antitumor immunity. We have engineered a double recombinant VV, coding human GM-CSF, and apoptosis-inducing protein apoptin (VV-GMCSF-Apo) for comparing with the earlier constructed double recombinant VV-GMCSF-Lact, coding another apoptosis-inducing protein, lactaptin, which activated different cell death pathways than apoptin. We showed that both these recombinant VVs more considerably activated a set of critical apoptosis markers in infected cells than the recombinant VV coding GM-CSF alone (VV-GMCSF-dGF): These were phosphatidylserine externalization, caspase-3 and caspase-7 activation, DNA fragmentation, and upregulation of proapoptotic protein BAX. However, only VV-GMCSF-Lact efficiently decreased the mitochondrial membrane potential of infected cancer cells. Investigating immunogenic cell death markers in cancer cells infected with recombinant VVs, we demonstrated that all tested recombinant VVs were efficient in calreticulin and HSP70 externalization, decrease of cellular HMGB1, and ATP secretion. The comparison of antitumor activity against advanced MDA-MB-231 tumor revealed that both recombinants VV-GMCSF-Lact and VV-GMCSF-Apo efficiently delay tumor growth. Our results demonstrate that the composition of GM-CSF and apoptosis-inducing proteins in the VV genome is very efficient tool for specific killing of cancer cells and for activation of antitumor immunity.

AB - Genetic modifications of the oncolytic vaccinia virus (VV) improve selective tumor cell infection and death, as well as activation of antitumor immunity. We have engineered a double recombinant VV, coding human GM-CSF, and apoptosis-inducing protein apoptin (VV-GMCSF-Apo) for comparing with the earlier constructed double recombinant VV-GMCSF-Lact, coding another apoptosis-inducing protein, lactaptin, which activated different cell death pathways than apoptin. We showed that both these recombinant VVs more considerably activated a set of critical apoptosis markers in infected cells than the recombinant VV coding GM-CSF alone (VV-GMCSF-dGF): These were phosphatidylserine externalization, caspase-3 and caspase-7 activation, DNA fragmentation, and upregulation of proapoptotic protein BAX. However, only VV-GMCSF-Lact efficiently decreased the mitochondrial membrane potential of infected cancer cells. Investigating immunogenic cell death markers in cancer cells infected with recombinant VVs, we demonstrated that all tested recombinant VVs were efficient in calreticulin and HSP70 externalization, decrease of cellular HMGB1, and ATP secretion. The comparison of antitumor activity against advanced MDA-MB-231 tumor revealed that both recombinants VV-GMCSF-Lact and VV-GMCSF-Apo efficiently delay tumor growth. Our results demonstrate that the composition of GM-CSF and apoptosis-inducing proteins in the VV genome is very efficient tool for specific killing of cancer cells and for activation of antitumor immunity.

KW - Animals

KW - Antineoplastic Agents

KW - Apoptosis Regulatory Proteins/genetics

KW - Apoptosis/genetics

KW - Biomarkers, Tumor/genetics

KW - Caspase 3/genetics

KW - Caspase 7/genetics

KW - Cell Death/genetics

KW - Cell Line, Tumor

KW - Cercopithecus aethiops

KW - DNA Fragmentation

KW - Female

KW - Genetic Vectors/genetics

KW - Granulocyte-Macrophage Colony-Stimulating Factor/genetics

KW - HSP70 Heat-Shock Proteins/genetics

KW - Humans

KW - Membrane Potential, Mitochondrial/genetics

KW - Mice

KW - Mice, SCID

KW - Neoplasms/genetics

KW - Oncolytic Viruses/genetics

KW - Phosphatidylserines/genetics

KW - Transgenes/genetics

KW - Up-Regulation/genetics

KW - Vaccinia virus/genetics

KW - Virus Replication/genetics

KW - bcl-2-Associated X Protein/genetics

KW - CANCER-CELLS

KW - DEATH

KW - VIROTHERAPY

KW - THERAPY

KW - ANTITUMOR IMMUNE-RESPONSE

KW - ONCOLYTIC ADENOVIRUS

KW - APOPTIN

KW - MECHANISMS

KW - CHEMOTHERAPY

KW - SOFT-TISSUE SARCOMA

UR - http://www.scopus.com/inward/record.url?scp=85029813204&partnerID=8YFLogxK

U2 - 10.1155/2017/3620510

DO - 10.1155/2017/3620510

M3 - Article

C2 - 28951871

AN - SCOPUS:85029813204

VL - 2017

SP - 3620510

JO - BioMed Research International

JF - BioMed Research International

SN - 2314-6133

M1 - 3620510

ER -