Where Killers Meet--Permeabilization of the Outer Mitochondrial Membrane during Apoptosis

Bender, Tom; Martinou, Jean‐Claude

doi:10.1101/cshperspect.a011106

Cited by 83 publications

(57 citation statements)

References 76 publications

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“…The proapoptotic BH123 proteins Bcl-2 associated x protein (Bax) and Bcl-2 homologous antagonist/killer (Bak) drive MOMP and are neutralized by antiapoptotic family members. BH3-only 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).…”

Section: Renal Cell Carcinoma (Rcc) Is Polyresistant To Chemo-and Radmentioning

confidence: 99%

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Gillissen

Richter

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonRenal cell carcinoma (RCC) is polyresistant to chemo-and radiotherapy and biologicals, including TNF-related apoptosisinducing 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 downregulation 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 downregulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (⌬⌿ m ) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ⌬⌿ m 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 ⌬⌿ m 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.Apoptotic cell death induced by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 2 plays an important role in immune surveillance and is a major immune defense mechanism against tumor cells. Consequently, the use of TRAIL, which preferentially kills cancer cells while sparing non-cancerous tissue, is a promising concept in anticancer therapy. Recombinant TRAIL and agonistic antibodies against the TRAIL receptors are therefore tested in clinical phase I and II studies (1-3).Binding of TRAIL to the death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) initiates receptor oligomerization and, via the adaptor protein Fas-associated protein with death domain (FADD), recruitment of the initiator caspase-8 to the death domain of the activated receptor (4, 5). Formation of this activation platform, the so-called death-inducing signaling complex, results in autocatalytic activation of caspase-8. In type I cells, active caspase-8 triggers, via direct proteolytic processing of caspase-3, a caspase cascade to induce apoptotic cell death. In type II cells, however, the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) prevents accumulation of active caspase-3 by marking it for proteasomal degradation (6). Therefore, in type II cells, efficient caspase-3 activation upon death receptor signaling requires amplification via the mitochondrial apoptosis pathway. Activation of the mitochondrial pathway is achieved by mitochondrial outer membrane permeabilization (MOMP) (7). Upon MOMP, the ...

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Section: Renal Cell Carcinoma (Rcc) Is Polyresistant To Chemo-and Radmentioning

confidence: 99%

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Gillissen

Richter

et al. 2017

Journal of Biological Chemistry

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“…[1][2][3] Although the Bcl-2 homology 3 (BH3)-only members such as Bid and Bim trigger apoptosis by binding to other family members, the prosurvival members block apoptosis by sequestering their pro-apoptotic relatives. Two remaining members, Bak and Bax, form the apoptotic pore within the mitochondrial outer membrane (MOM).…”

mentioning

confidence: 99%

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

et al. 2015

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Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak α9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that α9 does not line a pore. Bak (and Bax) activation allowed linkage of α9 to neighboring α9 segments, identifying an α9:α9 interface in Bak (and Bax) oligomers. Although the linkage pattern along α9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The α9:α9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when α9:α9 linkage in the membrane was combined with α6:α6 linkage on the membrane surface, the α6-α9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore. Mitochondrial permeabilization during apoptosis is regulated by the Bcl-2 family of proteins. 1-3 Although the Bcl-2 homology 3 (BH3)-only members such as Bid and Bim trigger apoptosis by binding to other family members, the prosurvival members block apoptosis by sequestering their pro-apoptotic relatives. Two remaining members, Bak and Bax, form the apoptotic pore within the mitochondrial outer membrane (MOM).Bak and Bax are globular proteins comprising nine α-helices. 4,5 They are activated by BH3-only proteins binding to the α2-α5 surface groove, 6-12 or for Bax, to the α1/α6 'rear pocket'. 13 Binding triggers dissociation of the latch domain (α6-α8) from the core domain (α2-α5), together with exposure of N-terminal epitopes and the BH3 domain. 6,7,14-16 The exposed BH3 domain then binds to the hydrophobic groove in another Bak or Bax molecule to generate symmetric homodimers. 6,7,14,17,18 In addition to dimerizing, parts of activated Bak and Bax associate with the lipid bilayer. 19 In Bax, the α5 and α6 helices may insert into the MOM, 20 although recent studies indicate that they lie in-plane on the membrane surface, with the hydrophobic α5 sandwiched between the membrane and a BH3:groove dimer interface. 7,[21][22][23] The dimers can be linked via cysteine residues placed in α6, 18,24,25 and more recently via cysteine residues in either α3 or α5, 6,21 allowing detection of the higherorder oligomers associated with pore formation. 26,27 However, whether these interactions are required for high-order oligomers and pore formation remains unclear.Like most Bcl-2 members, Bak and Bax are targeted to the MOM via a hydrophobic C-terminal region. The C terminus targets Bak to the...

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“…During apoptosis, an organized process of cytoskeleton breakdown, nuclear envelope disassembly, and nuclear DNA fragmentation occurs [54]. This causes shrinkage and an ordered removal of the cells, thus preventing leakage of cell contents to adjacent environment which can potentially trigger the damaging inflammation process [55]. The major executioners of apoptosis are caspases, whose activations can occur through several pathways.…”

Section: Apoptosis and Carcinogenesismentioning

confidence: 99%

“…The intrinsic pathway of apoptosis, also known as the mitochondrial pathway, begins when the permeability of the outer mitochondrial membrane increases in response to various cytotoxic stimuli and oxidative stresses [55]. The process of membrane permeabilization is regulated by the balance between pro-and anti-apoptotic proteins of the Bcl-2 family [56].…”

Section: Apoptosis and Carcinogenesismentioning

confidence: 99%

Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes

Tan

Ankathil

2015

Tumor Biol.

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Cervical cancer is a common malignancy which poses a significant health burden among women, especially those living in the developing countries. Although human papillomavirus (HPV) infection has been unequivocally implicated in the etiopathogenesis of the cancer, it alone is not adequate to contribute to the malignant transformation of cervical cells. Most HPV infections regress spontaneously, and only a small proportion of women have persistent infections which eventually lead to malignancy. This suggests that interplays between HPV infection and other cofactors certainly exist during the process of cervical carcinogenesis, which synergistically contribute to the differential susceptibility of an individual to the malignancy. Undoubtedly, host genetic factors represent a major element involved in such a synergistic interaction, and accumulating evidence suggests that polymorphisms in apoptosis-related genes play an important role in the genetic susceptibility to cervical cancer. This review consolidates the recent literatures on the role of common polymorphisms in apoptosis-related genes in genetic susceptibility to cervical cancer.

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Where Killers Meet--Permeabilization of the Outer Mitochondrial Membrane during Apoptosis

Cited by 83 publications

References 76 publications

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes

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