Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma-secretase inhibitor.
Primary effusion lymphoma (PEL) is a common cancer in AIDS patients closely associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Previously, we showed that KSHV latency associated nuclear antigen (LANA) stabilizes intracellular activated Notch1 (ICN) involved in maintenance of the malignant phenotype of KSHV infected PEL cells in vitro. The gamma-secretase inhibitor (GSI) which specifically blocks the production of ICN slows down the proliferation of the KSHV infected PEL cell lines BCBL1, BC3 as well as JSC1 in vitro. In this study, we extended these studies to explore the possibility that manipulation of the Notch signaling by GSI would prevent the growth of the PEL tumors in vivo. We observed that the onset of tumorigenesis of KSHV infected PELs was significantly delayed in GSI treated SCID mice harboring the PEL cell lines. We also found that GSI treatment resulted in necrosis as well as apoptosis in tumors generated by the xenotransplanted KSHV positive PEL cell lines. In contrast, GSI had no effect on mice harboring BJAB cells, a KSHV negative Burkitt's lymphoma cell line where ICN levels were negligible. Our study provides further evidence to suggest that targeted downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas.
Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, P.R. China.
Ke
K
Lan
Masanao
M
Murakami
Bharat
B
Bajaj
Rajeev
R
Kaul
Zhiheng
Z
He
Runliang
R
Gan
Michael
M
Feldman
Erle S
ES
Robertson
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000956:Antigens, Viral / Q000502:physiology; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000473:pathology; D045744:Cell Line, Tumor / Q000637:transplantation; D004151:Dipeptides / Q000627:therapeutic use*; D006566:Herpesviridae Infections; D004854:Herpesvirus 4, Human / Q000302:isolation & purification / Q000472:pathogenicity; D019288:Herpesvirus 8, Human / Q000302:isolation & purification / Q000472:pathogenicity*; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009336:Necrosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D011897:Random Allocation; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D014412:Tumor Virus Infections; D023041:Xenograft Model Antitumor Assays
D000956:Antigens, Viral; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D009363:Neoplasm Proteins; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D051881:Receptor, Notch1; C109540:latency-associated nuclear antigen; D053829:Amyloid Precursor Protein Secretases