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.
Highlights
The need to develop novel therapeutic strategies to treat relapsed/refractory aggressive lymphoma was delineated by the results of the prospective multicenter phase III Collaborative trial in relapsed aggressive lymphoma (CORAL) study [1,2,3]
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
Perhaps related to the acquirement of rituximab-chemotherapy resistance observed in our cell lines, we found a de-regulation of pro-apoptotic, anti-apoptotic, and inhibitor of apoptosis proteins www.impactjournals.com/oncotarget
Summary
The need to develop novel therapeutic strategies to treat relapsed/refractory aggressive lymphoma was delineated by the results of the prospective multicenter phase III Collaborative trial in relapsed aggressive lymphoma (CORAL) study [1,2,3]. Scientific efforts need to be focused in defining the resistance pathways utilized by lymphoma and identifying novel therapeutic strategies. To this end we developed several rituximab-resistant cellline (RRCL) models and found that the acquirement of rituximab resistance leads to resistance to multiple chemotherapy agents commonly used to treat B-cell lymphoma [4, 5]. Oligomerization of Bax and Bak is necessary for activation of the mitochondrial outer membrane permeability (MOMP) and subsequent release of cytochrome C following cytotoxic stress [8]. MOMP activation marks the commitment of cells to die by either caspase-dependent or -independent mechanism(s) and is tightly regulated by other partners such as the permeability transition pore complex (VDAC) or p53 [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
