Journal
ONCOTARGET
Volume 9, Issue 3, Pages 4020-4033Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.23425
Keywords
hexokinase II; rituximab-chemotherapy resistance; lymphoma; glucose metabolism
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Funding
- National Cancer Institute [5RO1CA136907-02]
- Developmental Funds from the Roswell Park Alliance Foundation
- Eugene and Connie Corasanti Lymphoma Research Fund
- Deutsche Krebshilfe
- Swiss National Science Foundation
- Else Kroner-Fresenius-Stiftung
- Deutsche Forschungsgemeinschaft [DFG EXC 1003]
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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.
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