PKD1 is critical for Epstein-Barr virus LMP1-induced protection of malignant B cells from cell death induced by rituximab.
Protein kinase D1 (PKD1 or PKCμ) is a serine/threonine kinase that contributes to malignant progression. Although B and T cells express multiple PKCs, modulation of PKC in association with EBV has not been evaluated. In this study we examined the effects of PKD1 as a cellular target of EBV latent membrane protein-1 (LMP1) on the response of malignant B cells to rituximab and doxorubicin. LMP1 up-regulated PKD1 in malignant B cells but not in T cells. Interestingly, LMP1 stabilized PKD1 protein through direct interaction, which contributed to the survival of malignant B cells. In the absence of PKD1, LMP1 was unable to up-regulate Mcl-1. Also, PH domain and activation loop of PKD1 was critical for LMP1-mediated cell survival. PKD1 knockdown was found to be an efficient strategy to overcome resistance caused by LMP1 expression. Therefore, PKD1 could be a molecular target for therapeutic intervention in EBV-associated B cell lymphoma treatment.
Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
Joo Hyun
JH
Kim
Won Seog
WS
Kim
Chaehwa
C
Park
D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D000069283:Rituximab; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000069283:Rituximab; D050396:TRPP Cation Channels; D014763:Viral Matrix Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus
B cell lymphoma; EBV; LMP1; PKD1/PKCμ; doxorubicin; rituximab