Oncotarget

Research Papers: Autophagy and Cell Death:

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

Jayshree L. Hirpara, Thomas Loh, Siok Bian Ng, Wee Joo Chng and Shazib Pervaiz _

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Oncotarget. 2016; 7:83964-83975. https://doi.org/10.18632/oncotarget.13336

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Abstract

Jayshree L. Hirpara1,2, Thomas Loh3, Siok Bian Ng4, Wee Joo Chng5 and Shazib Pervaiz1,6,7,8

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.


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