In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrialmediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over-expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target.
[1]Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA.
[2]Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA.
[3]Roswell Pk Canc Inst, Dept Pediat Oncol, Buffalo, NY 14263 USA.
[4]Fudan Univ, Shanghai Canc Ctr, Dept Med Oncol, Shanghai, Peoples R China.
[5]Philipps Univ Marburg, Dept Phys, Marburg, Germany.
[6]Univ Hosp Munster, Dept Med A, Hematol Oncol & Pneumol, Munster, Germany.
[7]Cells Mot, Cluster Excellence EXC 1003, Munster, Germany.
[8]Celgene, Summit, NJ USA.
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