Abstract
Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and biologicals, including TNF-related apoptosis-inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to TRAIL-induced apoptosis, in particular by down-regulation of the Bak-inhibitory Bcl-2 family protein Mcl-1. Here we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl-1 down-regulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (ΔΨm) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨm and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase-8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨm breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics, including TRAIL, in multiresistant cancers such as RCC.
Highlights
Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and biologicals, including TNF-related apoptosisinducing ligand (TRAIL)
Loss of ⌬⌿m and reactive oxygen species (ROS) production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic B cell lymphoma 2 (Bcl-2) family proteins Bcl-2 associated x protein (Bax) or Bcl-2 homologous antagonist/killer (Bak), indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade
To analyze the mechanism underlying the synergism of sorafenib and TRAIL in RCC, we investigated hallmarks of the mitochondrial apoptosis signaling cascade and death receptor signaling
Summary
Plays an important role in immune surveillance and is a major immune defense mechanism against tumor cells. Upon MOMP, the XIAP inhibitor second mitochondria-derived activator of caspase/direct IAPbinding protein with low pI (Smac/DIABLO) is released from the mitochondrial intermembrane space into the cytosol [8], where it inhibits XIAP and thereby prevents degradation of active caspase-3 (9 –11) Another important proapoptotic factor that is released into the cytosol upon MOMP is cytochrome c. Upon TRAIL-R ligation, MOMP is induced by caspase-8mediated cleavage and activation of BH3-interacting domain death agonist (Bid), a proapoptotic protein of the B cell lymphoma 2 (Bcl-2) family [13,14,15]. BH3only proteins activate Bax and Bak to induce MOMP indirectly by inhibiting prosurvival Bcl-2 proteins and/or via direct interaction with Bax and Bak [17, 18] Deregulation of these apoptosis signaling pathways accounts for resistance to anticancer therapies, including the biological agent TRAIL, which often serves as a prototypical targeted reagent to study apoptosis signaling in cancer cells. Accumulation of ROS overcomes the failure of TRAIL to activate caspase-8 in RCC cells and thereby enables TRAIL to induce apoptosis
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