Bortezomib Inhibits Extranodal Natural Killer/T Cell Lymphoma, Nasal Type by Targeting NF-κB Signaling Pathway

LI Jian-hua, ZHANG Li, FENG You, ZOU Li-qun

Abstract

To investigate the anti-tumor effect of bortezomib on extranodal natural killer/T cell lymphoma, nasal type (ENKTL).  Methods  SNK-6 cells were treated with different mass concentrations of bortezomib (0, 1, 2, 4, 5, 6 ng/mL) for 24, 48, 72 h, and different concentrations of nuclear factor-kappa B (NF-κB) signaling pathway inhibitor BAY11-7082 (0, 1, 2, 2.5, 5, 10, 20 μmol/L) for 24 h respectively, then the cell viability was measured by CCK8 kit and the half inhibitory concentration (IC50) was calculated. SNK-6 cells were treated with 30μmol/L Z-VAD-FMK (Pan-caspase inhibitor)+3ng/mL bortezomib, and 5, 10 μmol/L BAY11-7082+3 ng/mL bortezomib for 24 h respectively, then the cell viability was measured by CCK8 kit. After treatment of SNK-6 cells with different mass concentrations of bortezomib for 24 h, apoptosis was detected by AnnexinⅤ/PI flow cytometry; the expression of apoptosis-related protein Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl-2 and NF-κB signaling pathway key proteins P65 and P100/P52 were detected by Western blot.  Results  Bortezomib inhibited the proliferation of SNK-6 cells in a dose-dependent manner (P<0.05), and IC50﹝(2.87±0.06) ng/mL﹞at 24 h was lower than that at 48 h and 72 h (P<0.05). BAY11-7082 also inhibited the proliferation of SNK-6 cells with an IC50= (9.73±0.36) μmol/L at 24 h. The combination treatment indicated that Z-VAD-FMK could attenuate the inhibitory effect of bortezomib on the proliferation of SNK-6 cells (P<0.05), while BAY11-7082 could enhance the inhibitory effect of bortezomib on the proliferation of SNK-6 cells (P<0.05). After treatment of SNK-6 cells with bortezomib for 24 h, apoptosis-related protein Caspase-3 cleavage, PARP activation, and Bcl-2 cleavage; NF-κB signaling pathway-related protein P65 phosphorylation level decreased, and P52 decreased.  Conclusion  Bortezomib inhibits ENKTL cells proliferation by inhibiting NF-κB signaling pathway and induces apoptosis of ENKTL cells via mitochondria-mediated caspase pathway.

 

Keywords: Extranodal natural killer/T cell lymphoma, nasal type (ENKTL), Bortezomib, Apoptosis, NF-κB signaling pathway, BAY11-7082

 

Full Text:

PDF


References


SUN J， YANG Q， LU Z， et al. Distribution of lymphoid neoplasms in China analysis of 4638 cases according to the World Health Organization classification. Am J Clin Pathol，2012，138(3): 429–434.

SUZUKI R. NK/T cell lymphoma: updates in therapy. Curr Hematol Malig Rep，2018，13(1): 7–12.

BONIZZI G， KARIN M. The two NF-κB activation pathways and their role in innateand adaptive immunity. Trends Immunol，2004，25(6): 280–288.

MITCHELL S， VARGAS J， HOFFMANN A. Signaling via the NF-κB system. Wiley Interdiscip Rev Syst Biol Med，2016，8(3): 227–241.

HUANG Y， DE REYNIÈS A， DE LEVAL L， et al. Gene expression profiling identifiesemerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasaltype. Blood，2010，115(6): 1226–1237.

LIU X， WANG B， MA X， et al. NF-κB Activation through the alternative pathway correlates with chemoresistance and poor survival in extra-nodal NK/T-cell lymphoma, Nasal type. Jpn J Clin Oncol，2009， 39(7): 418–424.

MUJTABA T， DOU QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med，2011，12(67): 471–480.

SORS A， JEAN-LOUIS F， PELLET C， et al. Down-regulating constitutive activation of the NF-κB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood，2006， 107(6): 2354–2363.

PHAM LV， TAMAYO AT， YOSHIMURA LC， et al. Inhibition of constitutive NF-κB activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol，2003，171(1): 88–95.

SHEN L， AU WY， GUO T， et al. Proteasome inhibitor bortezomibinduced apoptosis in natural killer (NK)-cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation. Blood，2007，110(1): 469–470.

NAGATA H， KONNO A， KIMURA N， et al. Characterization of novel natural killer (NK)-cell and γδ T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood，2001，97(3): 708–713.

BONVINI P， ZORZI E， BASSO G， et al. Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ an aplastic large cell lymphoma. Leukemia，2007，21(40): 838–842.

LEONARD JP， FURMAN RR， COLEMAN M. Proteasome inhibition with bortezomib: a new therapeutic strategy for non-Hodgkin's lymphoma. Int J Cancer，2006，119(5): 971–979.

HIDESHIMA T， IKEDA H， CHAUHAN D， et al. Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells. Blood， 2009，114(5): 1046–1052.

ZOU P， KAWADA J， PESNICAK L， et al. Bortezomib induces apoptosis of epstein-barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. J Virol，2007，81(18): 10029–10036.

MORI N， YAMADA Y， IKEDA S， et al. Bay 11-7082 inhibits transcription factor NF-κB and induces apoptosis of HTLV-Ⅰ-infected T-cell lines and primary adult T-cell leukemia cells. Blood，2002，100(5): 1828–1834


Refbacks

  • There are currently no refbacks.