Up-regulation of hexokinase II contributes to rituximab-chemotherapy resistance and is a clinically relevant target for therapeutic development

// Juan J. Gu 1 , Anil Singh 1 , Kai Xue 4 , Cory Mavis 1 , Matthew Barth 3 , Vivek Yanamadala 2 , Peter Lenz 5 , Michael Grau 6, 7 , Georg Lenz 6, 7 , Myron S. Czuczman 8 and Francisco J. Hernandez-Ilizaliturri 1, 2 1 Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA 2 Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA 3 Department of Pediatric Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA 4 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China 5 Department of Physics, Philipps-University, Marburg, Germany 6 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany 7 Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany 8 Celgene, Summit, New Jersey, USA Correspondence to: Francisco J. Hernandez-Ilizaliturri, email: Francisco.hernandez@roswellpark.org Keywords: hexokinase II; rituximab-chemotherapy resistance; lymphoma; glucose metabolism Received: May 10, 2017      Accepted: November 26, 2017      Published: December 19, 2017 ABSTRACT 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.