Cytochrome c-mediated Apoptosis in Cells Lacking Mitochondrial DNA

Jiang, Shaojun; Cai, Jiyang; Wallace, Douglas C.; Jones, Dean P.

doi:10.1074/jbc.274.42.29905

Cited by 158 publications

(56 citation statements)

References 45 publications

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“…It is known that mtDNA depletion renders some cells more sensitive to apoptotic stimuli (Jiang et al, 1999) while opposite effects are observed in other cells (Dey and Moraes, 2000). We believe that the disparity in the literature on the role of mtDNA depletion on the tumorigenic properties of different cells (Morais et al, 1994;Cavalli et al, 1997;Arnould et al, 2002) probably relate to different nuclear gene targets affected in these cells, and their ability to resist apoptosis.…”

Section: Discussionmentioning

confidence: 52%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

231

271

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We have investigated mechanisms of mitochondrial stressinduced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca 2+ ] c , and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFb1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X L were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFb1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondriato-nucleus signaling pathway operating through increased [Ca 2+ ] c plays an important role in cancer progression and metastasis. Oncogene (2002Oncogene ( ) 21, 7839 -7849. doi:10.1038 Keywords: mitochondria; calcium signaling; cathepsin L; TGFb; tumor invasion; MAP kinases IntroductionThe role of mitochondria in carcinogenesis was initially suggested by Warburg et al. (1926;Warburg, 1956), based on the observation that number of experimentally induced rodent tumors exhibit reduced respiration-coupled oxidative metabolism and increased glycolysis. Since then, altered mitochondrial morphology, as well as changes in mitochondrial enzyme patterns and membrane transport systems, have been described in several tumor types (Zafar et al., 1982). Cell fusion studies (Jonasson et al., 1977;Howell and Sager, 1978;Giguere and Morais, 1981) also suggest that unknown cytoplasmic elements may play roles in carcinogenesis. Fusion between normal cytoplasm and karyoplasts from malignant phenotypes resulted in the ablation of tumorigenicity (Israel and Schaeffer, 1987) and conversely, the cytoplasm of the malignant phenotype could transfer the malignancy to the karyoplasts from normal cells (Israel and Schaeffer, 1988). Studies using mitochondrial DNA (mtDNA)-depleted tumor cells to evaluate the role of mtDNA, and thus mitochondrial function in tumorigenicity have yielded mixed results (Giguere and Morais, 1981;Morais et al., 1994;Cavalli et al., 1997;Cavalli and Liang, 1998;Hofhaus and Gattermann, 1999). Cavalli et al. (1997) found diminished tumor formation by glioblastoma cells following depletion of mtDNA (r 0 cells) with ethidium bromide treatment, while Morais et al. (1994) found increased capacity to p...

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Section: Discussionmentioning

confidence: 52%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

231

271

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“…[8][9][10][11][12] However, recent studies have challenged the central role of mitochondria in apoptosis and suggested that apoptosis can be induced by an ER stress pathway independent from mitochondria. 13,14 The ER plays a critical role in protein biosynthesis and maintenance of intracellular calcium homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…After injury, there is a loss of inner mitochondrial membrane potential (MMP) and release of factors such as apoptosis-initiating factor and cytochrome C. [8][9][10] Released cytochrome C activates caspase-9, which then activates downstream effector caspases, such as caspase-3 and -7. 11,12 Recent studies challenge the central role of mitochondria in apoptosis and suggest that some apoptotic signals may bypass mitochondria to directly activate caspases.…”

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confidence: 99%

Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation

et al. 2002

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Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphateribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease. (HEPATOLOGY 2002;36:592-601.)

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“…A major source of ROS is the mitochondria, in which cytochrome c release activates caspases that further increase ROS production. However, it is known that cellular sources of ROS are numerous including mitochondrial respiratory chain enzymes, NADPH oxidase, the cytochrome P-450 enzyme system, lipoxygenases, cyclo-oxygenases, xanthine oxidase, and nitric oxide synthase (Jiang et al, 1999;Bauer and Bauer, 1999;Tammariello et al, 2000). Moreover, NADPH dehydrogenase plays an important role in generating ROS during DOX treatment (Wong et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

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We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (DC m ) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001 -0.01 mM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3-and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

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Cytochrome c-mediated Apoptosis in Cells Lacking Mitochondrial DNA

Cited by 158 publications

References 45 publications

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

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