The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

Cavarretta, Ilaria T.; Neuwirt, Hannes; Untergasser, Gerold; Moser, Patrizia; Zaki, Mohamed H.; Steiner, Hannes; Rumpold, Holger; Fuchs, Dietmar; Hobisch, Alfred; Nemeth, Jeffrey A.; Čulig, Zoran

doi:10.1038/sj.onc.1210097

Cited by 96 publications

(68 citation statements)

References 59 publications

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“…Whether there is a cross-talk between these signaling pathways in melanoma cells is unknown and deserves to be investigated. In agreement with our findings is a recent report indicating that, in prostate cancer cells, Mcl-1 is regulated by the MAPK/ERK pathway (67).…”

Section: Discussionsupporting

confidence: 83%

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

Chetoui

Sylla

Gagnon-Houde

et al. 2008

Molecular Cancer Research

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Resistance of malignant melanoma cells to Fas-mediated apoptosis is among the mechanisms by which they escape immune surveillance. However, the mechanisms contributing to their resistance are not completely understood, and it is still unclear whether antiapoptotic Bcl-2 -related family proteins play a role in this resistance. In this study, we report that treatment of Fas-resistant melanoma cell lines with cycloheximide, a general inhibitor of de novo protein synthesis, sensitizes them to anti-Fas monoclonal antibody (mAb) -induced apoptosis. The cycloheximide-induced sensitization to Fas-induced apoptosis is associated with a rapid down-regulation of Mcl-1 protein levels, but not that of Bcl-2 or Bcl-xL. Targeting Mcl-1 in these melanoma cell lines with specific small interfering RNA was sufficient to sensitize them to both anti-Fas mAb-induced apoptosis and activation of caspase-9.

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Section: Discussionsupporting

confidence: 83%

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

Chetoui

Sylla

Gagnon-Houde

et al. 2008

Molecular Cancer Research

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“…Furthermore, previous research has shown that inhibition of just one of the signalling proteins in this pathway can induce ap-npg optosis through down-regulation of myeloid cell leukaemia 1 (MCL-1), an anti-apoptotic member of the B-cell lymphoma 2 (BCL-2) gene family [9,10]. MCL-1 is expressed in a fairly high percentage of prostate tumours [11,12], and the inhibition of ERK pathway-mediated signals, and consequently expression of MCL-1, might be a key target for treatment of advanced prostate cancer cells, as suggested by Cavarretta et al [13]. These observations form the basis for our hypothesis that targeting p42/p44 mitogen-activated protein kinase signalling pathways may inhibit tumour growth and progression in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

Huang¹,

Chen²,

Zhang³

et al. 2010

Asian J Androl

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The present study investigated the effects of the multikinase inhibitor sorafenib on androgen-independent cancer cells viability and intracellular signaling. Human androgen-independent PC-3 prostate cancer cells were treated with sorafenib. At concentration that suppresses extracellular signal-regulated kinase phosphorylation, sorafenib treatment reduced the mitochondrial transmembrane potential. Sorafenib also down-modulated the levels of myeloid cell leukemia 1, survivin and cellular inhibitor of apoptosis protein 2. Sorafenib induced caspase-3 cleavage and the mitochondrial release of cytochrome c. However, no nuclear translocation of apoptosis inducing factor was detected after treatment and the pan-caspase inhibitor Z-VAD-FMK had an obvious protective effect against the drug. In conclusion, sorafenib induces apoptosis through a caspase-dependent mechanism with down-regulated antiapoptotic proteins in androgen-independent prostate cancer cells in vitro.

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“…It has also been reported as an endogenous BAK inhibitor, whose inhibition can be disrupted by the tumor suppressor p53 and NOXA (18 -20). The regulatory mechanism remains unclear, whereas the deregulation is implicated in various hematopoietic and lymphoid cancers (21)(22)(23), which makes it an ideal therapeutic target for cancer treatment. The elucidation of the interaction between MCL-1 and BAK will provide more information for MCL-1-targeted drug design and screening.…”

mentioning

confidence: 99%

Heterodimerization of BAK and MCL-1 Activated by Detergent Micelles

Liu

Gehring

2010

Journal of Biological Chemistry

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BAK is a key protein mediating mitochondrial outer membrane permeabilization; however, its behavior in the membrane is poorly understood. Here, we characterize the conformational changes in BAK and MCL-1 using detergents to mimic the membrane environment and study their interaction by in vitro pulldown experiments, size exclusion chromatography, titration calorimetry, and NMR spectroscopy. The nonionic detergent IGEPAL has little impact on the structure of MCL-1 but induces a conformational change in BAK, whereby its BH3 region is able to engage the hydrophobic groove of MCL-1. Although the zwitterionic detergent CHAPS induces only minor conformational changes in both proteins, it is still able to initiate heterodimerization. The complex of MCL-1 and BAK can be disrupted by a BID-BH3 peptide, which acts through binding to MCL-1, but a mutant peptide, BAK-BH3-L78A, with low affinity for MCL-1 failed to dissociate the complex. The mutation L78A in BAK prevented binding to MCL-1, thus demonstrating the essential role of the BH3 region of BAK in its regulation by MCL-1. Our results validate the current models for the activation of BAK and highlight the potential value of small molecule inhibitors that target MCL-1 directly.

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The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

Cited by 96 publications

References 59 publications

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells

Heterodimerization of BAK and MCL-1 Activated by Detergent Micelles

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