Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

Zong, Wei‐Xing; Li, Chi; Hatzivassiliou, Georgia; Lindsten, Tullia; Yu, Qian-Chun; Yuan, Junying; Thompson, Craig B.

doi:10.1083/jcb.200302084

Cited by 549 publications

(488 citation statements)

References 49 publications

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“…Edelfosine did not upregulate Grp78/BiP (Figure 2b), a major ER chaperone that binds Ca 2 þ and promotes tumor proliferation, survival, metastasis and resistance to a wide variety of therapies (Li and Lee, 2006). ER stress has been shown to induce activation of Bax (Zong et al, 2003), and we found Bax activation in response to edelfosine treatment in pancreatic cancer cells, by using an anti-Bax monoclonal antibody that recognized the active form of Bax (Figure 2b). Previous studies have shown that ASK1-mediated JNK activation is crucial for ER-induced apoptosis (Nishitoh et al, 2002).…”

Section: Induction Of Apoptosis By Edelfosine and Other Alps In Humanmentioning

confidence: 86%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

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Section: Induction Of Apoptosis By Edelfosine and Other Alps In Humanmentioning

confidence: 86%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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“…It remains to analyze the molecular mechanisms by which TOM22 (and, possibly, other components of the TOM complex) is involved in the apoptotic outer membrane permeabilization. Finally, since Bax also localize to the endoplasmic reticulum to initiate apoptosis, 35 the mechanism of interaction of Bax with this organelle is still to be determined and in particular its relationship with the organelle import apparatus.…”

Section: Discussionmentioning

confidence: 99%

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

et al. 2006

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The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway. Apoptosis is a cell death program, which is central in many aspects to metazoan cell physiology and pathology. 1 Proteins of the Bcl-2 family are key players in the execution phase of apoptosis and their main functions is to control the release of apoptogenic proteins, such as cytochrome c (cyt c) and apoptosis inducing factor (AIF) from the mitochondria. 2 The Bcl-2 family is composed of antiapoptotic members such as Bcl-2 and proapoptotic proteins such as Bax or Bak, which share several domains of homology called BH. 1 In addition to these proteins, a third Bcl-2-related family of proteins have been identified as major amplifiers and/inducers of apoptosis. 2 The latter family has a homology to Bcl-2 limited to the BH3 domain and thus is called the BH3 only proteins. 2 The double knockout of Bax and Bak renders cells completely resistant to cell death 2 highlighting the essential role of these proteins during apoptosis.The determination of the solution structure of Bax showed its organization around nine a-helices (Ha1 to Ha9) 3 of which Ha2 contained most of the BH3 domain and Ha5 and Ha6, a putative pore forming domain that has been shown to be involved in the integration of Bax into the membrane. 4,5 Bax resides in an inactive state in the cytosol in many resting cells and is translocated to the mitochondria at the onset of apoptosis. 6 This translocation is associated with major conformational changes in Bax as both the amino-terminal end (N-T) and carboxy terminal end (C-T) become exposed facilitating its mitochondrial addressing and membrane insertion. 5,7 Bax mitochondrial membrane insertion and oligomerization is closely associated with the release into the cytosol of several intermembrane space proteins such as cyt c, second mitochondrial apoptotic factor (Smac) and AIF. 2 The nature of the different stimuli involved in the activation or in the inhibition of Bax is still largely unknown although this step remains one of the most critical points of control of the apoptotic program during which therapeutic interventions can be envisaged. 2 The mit...

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“…Thus, the ratio of Bax and Bak to Bcl-2 appears to be a key determinant of the levels of Ca 2 þ in the ER, as inferred from earlier studies. 93,97 In cells lacking Bax and Bak, uninhibited Bcl-2 leads to IP3R-1 hyperphosphorylation, enhanced ER Ca 2 þ release, and decreased steadystate ER Ca 2 þ stores. 94 Finally, Bid, Bik, and Bim, the upstream regulators of these Bcl-2 family members, are also influenced by proximal signals including ER stress.…”

Section: Gangliosides As Propagators Of the Er Stress-and Mitochondrimentioning

confidence: 99%

Gangliosides as apoptotic signals in ER stress response

d’Azzo

Tessitore²,

Sano

2006

Cell Death Differ

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Renewed attention has been given lately to gangliosides and to their function as intracellular messengers of the adaptive responses to stress. Gangliosides are vital components of cell membranes; therefore, deleterious consequences can result from changes in their chemical composition and concentration, that is, membrane dynamics and structure can be altered as can the behavior of other membrane proteins. The importance of gangliosides in human health is evident in neurodegenerative diseases associated with defects in their degradation. As key modulators of intracellular calcium flux, gangliosides are involved in cellular processes downstream of calcium signaling. In this review, we focus on the effect of ganglioside accumulation on the endoplasmic reticulum calcium homeostasis and on the integrity of the mitochondrial membranes. We discuss how these events elicit an apoptotic program that ultimately leads to cell death. Owing to interorganelle crosstalk, these events are not necessarily self-contained, and gangliosides may serve as the common factor.

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Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

Cited by 549 publications

References 49 publications

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

Gangliosides as apoptotic signals in ER stress response

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