Mitochondrial Release of Apoptosis-Inducing Factor and Cytochrome c During Smooth Muscle Cell Apoptosis

Granville, David J.; Cassidy, Brighid A.; Ruehlmann, Dietrich O.; Choy, Jonathan C.; Brenner, Catherine; Kroemer, Guido; Breemen, Cornelis van; Margaron, Philippe; Hunt, David W. C.; McManus, Bruce M.

doi:10.1016/s0002-9440(10)61696-3

Cited by 87 publications

(55 citation statements)

References 36 publications

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“…The cytoprotective effect of Ras/Raf/MEK/ERK signaling cascade is partly mediated by the inhibition of degradation and subsequent stabilization of Mcl-1 proteins levels (20,21). Mcl-1 is one of the major antiapoptotic proteins expressed in multiple myeloma cells, and resistance to drug treatment has been associated with high levels of Mcl-1 expression.…”

Section: Downregulation Of Mcl-1 Protein Levels Is Critical For Sorafmentioning

confidence: 99%

Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model

et al. 2012

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Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multityrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138 þ -enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138 þ -enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737. Cancer Res; 72(20); 5348-62. Ó2012 AACR.

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Section: Downregulation Of Mcl-1 Protein Levels Is Critical For Sorafmentioning

confidence: 99%

Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model

et al. 2012

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“…Also, displacement of the organelle could facilitate translocation of mitochondrial proteins, such as apoptosis-inducing factor (AIF) which binds to DNA and triggers its destruction, to the nucleus (Susin et al 2000). Moreover, the modifications that undergo mitochondria like size reduction or pyknosis could be related to the release of mitochondrial proteins (e.g., AIF, cytochrome c) observed in apoptosis (Granville et al 2001). Further studies are necessary to elucidate the relative role of these events and the mechanisms by which estrogens exert an inhibitory effect upon them.…”

Section: Role Of Ers In the Antiapoptotic Effects Of Ementioning

confidence: 99%

17β-Estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway

Vasconsuelo

Milanesi²,

Boland³

2007

Journal of Endocrinology

101

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Estrogens can regulate apoptosis in various cellular systems. The present study shows that 17b-estradiol (E 2 ), at physiological concentrations, abrogates DNA damage, poly (ADP-ribose) polymerase cleavage, and mitochondrial cytochrome c release induced by H 2 O 2 or etoposide in mouse skeletal muscle C2C12 cells. This protective action, which involved PI3K/Akt activation and Bcl-2 associated death agonist (BAD) phosphorylation, was inhibited by antibodies against the estrogen receptor (ER) a or b isoforms, or transfecting siRNA specific for each isoform. The inhibition of the antiapoptotic action of E 2 at the mitochondrial level was more pronounced when ER-b was immunoneutralized or suppressed by mRNA silencing, whereas transfection of C2C12 cells with either ER-a siRNA or ER-b siRNA blocked the activation of Akt by E 2 , suggesting differential involvement of ER isoforms depending on the step of the apoptotic/survival pathway evaluated. These results indicate that E 2 exerts antiapoptotic effects in skeletal muscle cells which are mediated by ER-b and ER-a and involve the PI3K/Akt pathway. Journal of Endocrinology (2008) 196, 385-397 IntroductionThe estrogen 17b-estradiol (E 2 ) is a steroid hormone whose actions involve genomic and non-genomic mechanisms (Bjornstrom & Sjoberg 2005). It is generally accepted that the majority of the effects of the hormone are mediated via two estrogen receptors (ERs), namely ER-a and ER-b, which are members of the nuclear receptor superfamily, by regulating nuclear estrogen responsive genes (Evans 1988, Tsai & O'Malley 1994, Beato et al. 1996, Pettersson et al. 2000, Hall et al. 2001, Hewitt & Korach 2002. Also, several investigators have pointed out the possibility that the ER could be non-classically associated with intracellular membranes (Parikh et al. 1980, Watson & Muldoon 1985, Muldoon et al. 1988, Monje & Boland 1999, Watson et al. 1999. Moreover, there is evidence showing that ER-a and ER-b may be located in the plasma membrane (Luconi et al. 1999, Norfleet et al. 2000, Ropero et al. 2002, Li et al. 2003 and mitochondrial compartments (Zheng & Ramirez 1999, Horvat et al. 2001, Monje & Boland 2002, Yang et al. 2004, Solakidia et al. 2005. In addition, the non-genomic events triggered by E 2 suggest the ability of the hormone to activate extranuclear receptors (Bjornstrom & Sjoberg 2005). Among the rapid nontranscriptional actions of E 2 , the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been shown in various cellular lines (Fernando & Wimalasena 2004, Guo et al. 2006. PI3K regulates phosphoinositide metabolism and is responsible for the generation of phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ;Vanhaesebroeck et al. 2001, Osaki et al. 2004. The activation of PI3K results in PIP 3 -mediated activation of the serine-threonine kinase Akt by phosphorylation. In turn, phospho-Akt modulates the function of numerous substrates involved in the regulation of cell functions as for example apoptosis (Coffer et al. 1998, Vanhaesebroeck et al....

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“…Western blots on human coronary arteries were performed as described elsewhere (15,16). Briefly, fresh frozen coronary arteries with advanced atherosclerosis and TVD were obtained from the St. Paul's Hospital Cardiovascular Registry.…”

Section: Western Blotmentioning

confidence: 99%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

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Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD).Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle ␣-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0 -5؉/5؉ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle ␣-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.

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Mitochondrial Release of Apoptosis-Inducing Factor and Cytochrome c During Smooth Muscle Cell Apoptosis

Cited by 87 publications

References 36 publications

Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model

Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model

17β-Estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

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