Up-regulation of hexokinase II contributes to rituximab-chemotherapy resistance and is a clinically relevant target for therapeutic development
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Juan J. Gu1, Anil Singh1, Kai Xue4, Cory Mavis1, Matthew Barth3, Vivek Yanamadala2, Peter Lenz5, Michael Grau6,7, Georg Lenz6,7, Myron S. Czuczman8 and Francisco J. Hernandez-Ilizaliturri1,2
1Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
2Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA
3Department of Pediatric Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
4Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
5Department of Physics, Philipps-University, Marburg, Germany
6Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
7Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
8Celgene, Summit, New Jersey, USA
Francisco J. Hernandez-Ilizaliturri, email: [email protected]
Keywords: hexokinase II; rituximab-chemotherapy resistance; lymphoma; glucose metabolism
Received: May 10, 2017 Accepted: November 26, 2017 Published: December 19, 2017
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 mitochondrial-mediated 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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