PKD1 is critical for Epstein–Barr virus LMP1-induced protection of malignant B cells from cell death induced by rituximab

Abstract

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.

Keywords::

• EBV
• B cell lymphoma
• LMP1
• PKD1/PKCμ
• rituximab
• doxorubicin

Acknowledgement

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011 – 0010951).

Potential conflict of interest

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Supplementary material available online

Supplementary Figures 1–5, showing cell transfection conditions and further results.