Drp1 Activation Overcomes Diffuse Large B-Cell Lymphoma Cells Radioresistance

Abstract 5121

Mitochondria undergo fusion and fission in response to physiological or pathological changes. Mitochondrial fusion is regulated by mitofusin-1 and 2 (MFN-1/2) and optic atrophy 1(OPA-1), whereas, mitochondrial fission (or fragmentation) is controlled by a Dynamin-related protein 1 (Drp1). Drp1 activation is triggered by dephosphorylation of Drp1 on its serine 637 site. Recent studies demonstrated that Drp1 activation plays an important role in mitochondrial fragmentation-induced cell death. The phosphorylation of Drp1 by serine kinase inhibits its GTPase activity and prevents mitochondrial fragmentation. Inhibition of Drp1 activation or loss of Drp1 function leads to slow down apoptosis and necrosis.

Recent reports showed that patients who received consolidative radiotherapy (RT) combine R-CHOP had significant better 5-year event-free and overall survival rates than patients with diffuse large B-cell lymphoma who did not receive RT combination therapy. Although RT combination therapy significant increased survival of DLBCL, the mechanisms of RT induced cell death are reminded unclear.

In this study, we investigated the roles of Drp1 activation in the sensitivity of DLBCL cells to radiotherapy. Radiation causes damage in both nuclear and mitochondrial DNAs and generation of reactive oxygen species (ROS) followed by caspase activation. In the radio-resistant DLBCL cells, radiation induced activation of Drp1, and led to mitochondrial fragmentation, caspase-3 activation and cell death. However, the sensitive DLBCL cells underwent cytochrome c release, caspase-3 activation and PARP cleavage but not the activation of Drip1. To confirm the role of Drp1 activation in radiation-induced cell death on radio-resistant cells, Drp1 was dephosphorylated by a serine kinase inhibitor STS. Co-treatment of radio-resistant DLBCL cells with STS and radiation greatly enhanced mitochondrial fragmentation and significantly increased the sensitivity of radio-resistant DLBCL cells to radiation-induced caspase-3 activation, PARP cleavage and apoptotic cell death. However, co-treatment with STS did not further increase the sensitivity of radio-sensitive cells to caspsase-3 activation and cell death. Our data indicate that radiation-induced cell death in radio-resistant DLBCL cells is regulated by Drp1. We therefore propose that Drp1 could be a potential target for overcoming radio-resistance.