Rituximab is the first line drug to treat
non Hodgkin's lymphoma (B-NHL) alone or in combination with
chemotherapy. However, 30-40% of B-NHL patients are unresponsive to
rituximab or resistant after
therapy. Human
phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of
B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited
rituximab-mediated
complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of
rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-
acute lymphocytic leukemia (B-ALL) cells to R-CDC. During
rituximab-mediated
complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced
calcium flux and
reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in
B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the
rituximab in
B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of
caspase-3 and
caspase-9. Considering that hPEBP4 conferred cellular resistance to
rituximab treatment and was preferentially expressed in
lymphoma tissue, it could be a potential valuable target for adjuvant
therapy for
B-cell lymphoma.