Interleukin-3 Withdrawal Induces an Early Increase in Mitochondrial Membrane Potential Unrelated to the Bcl-2 Family

Khaled, Annette R.; Reynolds, Della; Young, Howard A.; Thompson, Craig B.; Muegge, Kathrin; Durum, Scott K.

doi:10.1074/jbc.m006391200

Cited by 82 publications

(64 citation statements)

References 46 publications

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“…Growth factors also regulate the glycolytic metabolism of cells thus promoting energy production. As shown in this report and in previous ones, 18,19,24,25 growth factor withdrawal induces a metabolic slowdown that is revealed by a drop in glucose uptake, lactate production and in intracellular ATP concentration. IL-3 also regulates the expression of key genes involved in the control of glucose metabolism such as Glut1, hexokinase 2 or phospho-fructo kinase.…”

Section: Discussionsupporting

confidence: 84%

Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following IL-3-starvation

et al. 2002

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IL-3 regulates the glycolytic pathway. In Baf-3 cells IL-3 starvation leads to a decrease in glucose uptake and in lactate production. To determine if there is a link between the decreased metabolism induced by growth factor-starvation and the induction of cell death, we have compared the cell death characteristics and the metabolic modifications induced by IL-3-deprivation or glucose-deprivation in Baf-3 cells. We show that in both conditions cells die by an apoptotic process which involves the activation of similar Caspases. Different metabolic parameters (i.e. intracellular ATP levels and lactate accumulation in the culture medium) were measured. We show that IL-3 deprivation leads to a partial decrease in lactate production in contrast to glucose deprivation that completely inhibits lactate production. Similarly following IL-3-starvation a significant drop in the intracellular ATP levels in live cells is observed only after 16 h when a large fraction, more than 50 per cent of cells, is already apoptotic. On the contrary, glucose deprivation is followed by an abrupt decrease in ATP levels in the first 2 h of treatment. However, in the presence of IL-3, cells are able to survive for an extended time in these conditions since 70% of cells survived with low ATP levels for up to 16 h. This was not due to partial inhibition of the apoptotic process by the low level of ATP as glucose-deprivation in the absence of IL-3 led to faster death kinetics of Baf-3 cells compared with IL-3 starvation only. These results indicate that the drop in ATP levels and the triggering of apoptosis can be dissociated in time and that when the glycolytic pathway is strongly inhibited, cells are able to survive with relatively low ATP levels if IL-3 is present. Finally we show that induction of bcl-x by IL-3 protects cells from glucose-deprivation induced cell death.

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Section: Discussionsupporting

confidence: 84%

Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following IL-3-starvation

et al. 2002

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“…The role of this protein for the increase in mitochondrial membrane potential is well established in mammalian cells. It is known that mitochondrial membrane hyperpolarization is dependent on the utilization of glycolytic ATP by oligomycin-sensitive F0-F1 ATPase in the reverse mode and at the same time other transporters are also acting in the reverse mode 36,37 This hyperpolarization has been interpreted as being independent or part of the apoptotic process in mammalian cells. 33,38 In case of leishmanial cells, mitochondrial hyperpolarization occurred before the increase ) and with CED-3/CPP32 group of protease inhibitor, VAD-fmk prior to treatment with CPT for 3.5 h (IV), respectively.…”

Section: Discussionmentioning

confidence: 99%

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

et al. 2004

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The parasites of the order kinetoplastidae including Leishmania spp. emerge from most ancient phylogenic branches of unicellular eukaryotic lineages. In their life cycle, topoisomerase I plays a significant role in carrying out vital cellular processes. Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces programmed cell death (PCD) both in the amastigotes and promastigotes form of L. donovani parasites. CPT-induced cellular dysfunction in L. donovani promastigotes is characterized by several cytoplasmic and nuclear features of apoptosis. CPT inhibits cellular respiration that results in mitochondrial hyperpolarization taking place by oligomycin-sensitive F0-F1 ATPase-like protein in leishmanial cells. During the early phase of activation, there is an increase in reactive oxygen species (ROS) inside cells, which causes subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents like GSH. Endogenous ROS formation and lipid peroxidation cause eventual loss of mitochondrial membrane potential. Furthermore, cytochrome c is released into the cytosol in a manner independent of involvement of CED3/CPP32 group of proteases and unlike mammalian cells it is insensitive to cyclosporin A. These events are followed by activation of both CED3/CPP32 and ICE group of proteases in PCD of Leishmania. Taken together, our study indicates that different biochemical events leading to apoptosis in leishmanial cells provide information that could be exploited to develop newer potential therapeutic targets.

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“…Changes in pH, addition of detergents and mild heat shock have also been observed to cause a conformational change in Bax, but not insertion into membranes 356,357 . The BH3-only proteins can displace the loosened 9 helix from the hydrophobic pocket, and Bax can insert into the OMM.…”

Section: Figure 116: Bax Activation Involves a Conformational Changementioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Interleukin-3 Withdrawal Induces an Early Increase in Mitochondrial Membrane Potential Unrelated to the Bcl-2 Family

Cited by 82 publications

References 46 publications

Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following IL-3-starvation

Decreased glycolytic metabolism contributes to but is not the inducer of apoptosis following IL-3-starvation

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

Role of the pro-survival molecule Bfl-1 in melanoma

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