The oncolytic activity of Newcastle disease virus NDV-HUJ on chemoresistant primary melanoma cells is dependent on the proapoptotic activity of the inhibitor of apoptosis protein Livin.
Patients with advanced melanoma usually do not benefit from conventional chemotherapy treatment. There is therefore a true need for a new kind of therapy for melanoma. One factor responsible for the poor prognosis of melanoma is the inhibitor of apoptosis protein (IAP) family member Livin. In this study, we applied a novel approach for the treatment of melanoma, using a unique strain of the oncolytic Newcastle disease virus (NDV-HUJ). We found that, unlike chemotherapeutic drugs, NDV-HUJ, a one-cycle replicating virus, overcomes the resistance to apoptosis of melanoma primary cultures that over express the Livin protein. In contrast, melanoma tumor cells that do not express Livin are relatively resistant to NDV-HUJ treatment. Furthermore, we show that NDV-HUJ-induced oncolysis is attributed to the dual function of Livin: although Livin inhibits apoptosis through the inhibition of caspases, under the robust apoptotic stimulation of NDV-HUJ, caspases can cleave Livin to create a truncated protein with a paradoxical proapoptotic activity. Thus, NDV-HUJ is a potent inducer of apoptosis that can overcome the antiapoptotic effect of Livin and allow cleavage of Livin into the proapoptotic tLivin protein. Moreover, the results indicate that the interferon system, which is functional in melanoma, is not involved in NDV-induced oncolysis. Taken together, our data offer the possibility of a new viral oncolytic treatment for chemoresistant melanoma.
Department of Virology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Itay
I
Lazar
Barak
B
Yaacov
Tamar
T
Shiloach
Elad
E
Eliahoo
Luna
L
Kadouri
Michal
M
Lotem
Riki
R
Perlman
Zichria
Z
Zakay-Rones
Amos
A
Panet
Dina
D
Ben-Yehuda
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000502:physiology*; D009522:Newcastle disease virus / Q000472:pathogenicity*; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000472:pathogenicity*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D020169:Caspases