Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas

// Jayshree L. Hirpara 1,2 , Thomas Loh 3 , Siok Bian Ng 4 , Wee Joo Chng 5 and Shazib Pervaiz 1,6,7,8 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Experimental Therapeutics Program, Cancer Science Institute, National University Healthcare System, Singapore 3 Department of Otolaryngology, National University Healthcare System, Singapore 4 Department of Pathology, National University Healthcare System, Singapore 5 Cancer Science Institute, National University Healthcare System, Singapore 6 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 7 National University Cancer Institute, National University Healthcare System, 8 School of Biomedical Sciences, Curtin University, Perth, Australia Correspondence to: Shazib Pervaiz, email: // Keywords : DLBCL, apoptosome, Apaf-1, lipid rafts, ROS, Autophagy Received : April 15, 2016 Accepted : November 08, 2016 Published : November 14, 2016 Abstract Resistance to chemotherapy remains a challenge in the clinical management of diffuse B cell lymphomas despite aggressive chemotherapy such as CHOP and monoclonal CD20. Here we provide evidence that the apoptosome adaptor protein, Apaf-1, is mislocalized in primary cells derived from patients with diffuse large B cell lymphomas (DLBCL). Whereas, the total expression of Apaf-1 did not change, its sub-cellular localization was significantly different in DLBCL, compared to T cell lymphomas as well as cells derived from reactive lymphadenopathy biopsies. As expected, Apaf-1 was detected in the cytosolic fractions of non-B cell lymphomas and non-cancerous tissues; however, in B cell derived lymphomas the protein was detected in membrane raft sub-domains rather than the cytosol. Disruption of lipid raft structures resulted in the redistribution of Apaf-1 to the cytosol and restored apoptosis sensitivity of DLBCL. Furthermore, we identified novel small molecule compounds that target DLBCL by promoting Apaf-1 release form lipid rafts via mechanisms that involve an increase in intracellular reactive oxygen species production. Taken together, our results implicate Apaf-1 mislocalization as a potential diagnostic and prognostic marker for DLBCL, and provide a novel therapeutic strategy for circumventing the drug refractory nature of this sub-class of B cell lymphoma.