Localization of death receptor 4 in lipid rafts sensitizes chronic lymphocytic leukemia to chemotherapeutic drug mediated apoptosis

Apoptosis or programmed cell death is a tightly controlled process essential for normal tissue homeostasis [1]. Aberrant regulation of apoptosis can lead to cancer. Tumor cells often acquire resistance to normal apoptotic signals allowing for uncontrolled cell growth [2]. The process of targeting the apoptotic pathway in tumor cells while sparing normal cells is of interest in cancer therapy [3]. Such targeted therapy to induce apoptosis in cancer cells has emerged as a strategy to more effectively treat patients with cancer and reduce toxicity. Apoptotic cell death can be initiated by either the intrinsic mitochondrial pathway or the extrinsic death receptor pathway [4]. Death receptors are key components in the extrinsic apoptotic pathway [5]. Their activation due to ligand binding or receptor clustering and aggregation triggers an extrinsic apoptotic signaling pathway leading to apoptosis [6]. Death receptor 4 (DR4) and DR5 are members of the tumor necrosis factor related apoptosisinducing ligand (TRAIL) receptor superfamily sharing conserved cytoplasmic death domains essential for inducing apoptosis. Upon binding to TRAIL, DR4 and DR5 recruit the adapter molecule Fasassociated death domain (FADD), which through its death domain interacts with pro-caspases 8 and 10 to form a death-inducing signaling complex (DISC). DISC then stimulates the proteolytic activation of caspase 8, initiating a cascade of downstream caspase activation which leads to apoptosis [7–9]. There are many compounds/agents that increase TRAIL death receptor expression, an action that leads to priming to TRAIL-mediated synergistic apoptotic response [10,11], suggesting that modulation of death receptors by cancer therapeutic agents has implications for cancer therapy. In this issue of Leukemia and Lymphoma, Gibson and co-workers [12] demonstrate a higher level of DR4 expression in chronic lymphocytic leukemia (CLL) cells. In TRAIL resistant CLL cells, only activation of DR4 provides an increase in fludarabine induced apoptosis. The authors suggest that this is mediated in part by the localization of DR4 but not DR5 in lipid rafts following TRAIL and fludarabine treatment. DR4 is found in lipid rafts without TRAIL activation likely due to palmitoyation. Upon TRAIL treatment, DR4 levels are enriched in lipid rafts. DR5 lacks this palmitoyation and is less likely to localize in lipid rafts. Increased DR4 in lipid rafts is associated with formation of DISC proteins and activation of the apoptotic pathway. Since DR5 is more diffusely located in the plasma membrane, it cannot form the DISC and additionally induce apoptosis. This potential mechanism will be the focus of future investigation. This preference for DR4 activation leading to increased fludarabine induced apoptosis was also observed following SAHA (suberoylanilide hydroxamic acid), PS-341, and chlorambucil treatment in primary CLL cells. Thus, CLL cells selectively activate DR4 partially mediated through its localization to lipid rafts leading to apoptosis when combined with chemotherapeutic drugs. Altogether, these data are very interesting, and an understanding of the mechanism of the modulation of death receptors in lipid rafts will help in sensitizing CLL and other