The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents?

Forte, Michael; Bernardi, Paolo

doi:10.1038/sj.cdd.4401957

Cited by 34 publications

(22 citation statements)

References 49 publications

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“…For instance, A2780, SK-OV-3, and Caov-3 consistently exhibited loss of membrane potential in response to SHetA2, whereas OVCAR-3, which was equally sensitive to the drug, did not. Outer mitochondrial membrane permeabilization induced by the Bax or Bak proteins seems to be a separate, but integrated, mechanism from IMM permeabilization (12). Therefore, outer mitochondrial membrane permeabilization induced by Flex-Hets may lead to IMM permeabilization, depending on the state of the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Liu

Hannafon

Gill

et al. 2007

Molecular Cancer Therapeutics

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Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x L , and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het -induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent FlexHet mitochondrial or apoptosis effects. Bcl-2 and Bcl-x L levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis.

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Section: Discussionmentioning

confidence: 99%

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Liu

Hannafon

Gill

et al. 2007

Molecular Cancer Therapeutics

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“…According to our data, CypD and Bcl2 cooperate in inhibiting MPT-independent CytC release from mitochondria. Such MPT-independent CytC release from mitochondria appears to be prevalent during various forms of apoptosis (17), whereas MPT-induced CytC release occurs primarily during necrosis (15). In addition, calcium, which is known to promote CypD binding to the ANT (7,9), is mandatory for MPT opening (8).…”

Section: Discussionmentioning

confidence: 99%

“…Because of the role of CypD in regulation of the MPT, the attempt has been made to relate the anti-apoptotic effect of CypD in cancer cells to the MPT (5). The MPT has been suggested as one of the mechanisms of release of CytC and other apoptogenic factors from mitochondria during apoptosis (17). In view of the pro-apoptotic effect of MPT opening, the anti-apoptotic effect of CypD, a key positive regulator of the MPT, seems controversial.…”

mentioning

confidence: 99%

Cyclophilin D Interacts with Bcl2 and Exerts an Anti-apoptotic Effect

Eliseev

Malecki

Lester

et al. 2009

Journal of Biological Chemistry

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Cyclophilin D (CypD) is a mitochondrial immunophilin and a key positive regulator of the mitochondrial permeability transition (MPT). Several reports have shown that CypD is overexpressed in various tumors, where it has an anti-apoptotic effect. Because the MPT is a cell death-inducing phenomenon, we hypothesized that the anti-apoptotic effect of CypD is independent of the MPT but is due to its interaction with some key apoptosis regulator, such as Bcl2. Our data indicate that CypD indeed interacts with Bcl2 as confirmed with co-immunoprecipitation, pulldown, and mammalian two-hybrid assays. A cyclophilin D inhibitor, cyclosporine A, disrupts the CypD-Bcl2 interaction. CypD enhances the limiting effect of Bcl2 on the tBid-induced release of cytochrome c from mitochondria, which is not mediated via the MPT. Gain-and loss-of-function experiments confirm that CypD has a limiting effect on cytochrome c release from mitochondria and that such an effect of CypD is cyclosporine A-and Bcl2-dependent. On a cellular level, overexpression or knockdown of CypD respectively decreases or increases cytochrome c release from mitochondria and overall cell sensitivity to apoptosis progressing via the "intrinsic" pathway. Therefore, we here describe a novel function of CypD as a Bcl2 collaborator and an inhibitor of cytochrome c release from mitochondria independent of the MPT. This function of CypD may explain the anti-apoptotic effect of this protein observed in various cancer cells. The fact that some tumors overexpress CypD suggests that this may be an additional mechanism of suppression of apoptosis in cancer.

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“…9 The process of mitochondrial inner membrane permeabilization (MIMP) is often associated with permeability transition pore (PTP) opening. [10][11][12][13] The PTP is a multi-protein complex which as yet is poorly defined at the molecular level. Previously the PTP was thought to comprise the adenosine nucleotide translocator and cyclophilin D on the IMM complexed with voltage dependent anion channel and the peripheral benzodiazepine receptor on the OMM.…”

mentioning

confidence: 99%

A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

et al. 2008

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Primary chronic lymphocytic leukemia (CLL) cells are exquisitely sensitive to ABT-737, a small molecule BCL2-antagonist, which induces many of the classical biochemical and ultrastructural features of apoptosis, including BAX/BAK oligomerization, cytochrome c release, caspase activation and chromatin condensation. Surprisingly, ABT-737 also induces mitochondrial inner membrane permeabilization (MIMP) resulting in mitochondrial matrix swelling and rupture of the outer mitochondrial membrane (OMM), so permitting the rapid efflux of cytochrome c from mitochondrial cristae and facilitating rapid caspase activation and apoptosis. BAX and BAK appear to be involved in the OMM discontinuities as they localize to the OMM break points. Notably, ABT-737 induced mitochondrial matrix swelling and OMM discontinuities in other primary B-cell malignancies, including mantle cell, follicular and marginal zone lymphoma cells but not in several cell lines studied. Thus, we describe a new paradigm of apoptosis in primary B-cell malignancies, whereby targeting of BCL2 results in all the classical features of apoptosis together with OMM rupture independent of caspase activation. This mechanism may be far more prevalent than hitherto recognized due to the failure of most methods, used to measure apoptosis, to recognize such a mechanism.

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The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents?

Cited by 34 publications

References 49 publications

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Cyclophilin D Interacts with Bcl2 and Exerts an Anti-apoptotic Effect

A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

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