Cisplatin (CDDP) sensitizes human osteosarcoma cell to Fas/CD95-mediated apoptosis by down-regulating FLIP-L expression

Kinoshita, Hirokazu; Yoshikawa, Hideshi; Shiiki, Kazuhiko; Hamada, Y.; Nakajima, Yasuo; Tasaka, Kachio

doi:10.1002/1097-0215(20001215)88:6<986::aid-ijc23>3.0.co;2-b

Cited by 69 publications

(48 citation statements)

References 28 publications

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“…First, as all eight human osteosarcoma cell lines tested in this study, constitutively express Fas (Hamada et al, 1999;Kinoshita et al, 2000;Lafleur et al, 2001), including Takao and OS690 cells (data not shown), we investigated expression of FasL and Fas for apoptosis-related genes upregulated by FR901228. As for FasL, there was no detectable FasL mRNA expression observed in OST cells, while treatment with 10 nM FR901228 induced expression of FasL gene as early as 2 h after treatment by reverse transcriptase-polymerase chain reaction (RT-PCR) ( Figure 4a).…”

Section: Fr901228 Upregulates Fasl Expression and Activates Caspase-8mentioning

confidence: 97%

FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells

et al. 2003

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We investigated the antitumor effects of FR901228, a HDAC inhibitor, on human osteosarcoma cells, in vitro and in vivo to explore its possible utility in the treatment of pediatric bone cancers. FR901228 caused marked growth inhibition with a 50% inhibitory concentration of 1.2-7.3 nM and induction of apoptosis in all eight osteosarcoma cell lines tested. These effects of FR901228 were also observed in vivo xenograft models on BALB/c nude mice, and treatment with 5.6 mg/kg/day resulting in a >70% reduction in the mean final tumor volume compared with the mean initial tumor volume. TUNEL assays demonstrated extensive apoptosis in tumor sections of mice treated with FR901228. Induction of apoptosis was preceded by increased expression of Fas ligand (FasL) mRNA, resulting in expression of membrane-bound FasL, which was followed by sequential activation of caspase-8 and -3. The level of apoptosis induction was reduced using a neutralizing anti-FasL antibody and overexpression of either the dominantnegative FADD or the viral FLICE inhibitory protein.Furthermore, treatment with a suboptimal dose of FR901228 greatly sensitized osteosarcoma cells to agonistic anti-Fas antibody-mediated apoptosis. These findings suggest that FR901228 is a highly promising antitumor agent against osteosarcoma, inducing apoptosis by the activation of the Fas/FasL system.

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Section: Fr901228 Upregulates Fasl Expression and Activates Caspase-8mentioning

confidence: 97%

FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells

et al. 2003

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“…Some of these agents include DNA damaging agents and chemotherapeutic drugs (such as cisplatin and Oxaliplatin), topoisomerase I inhibitors (camptothecin, 9-nitrocamptothecin (9NC), irinotecan) (Kinoshita et al, 2000;Chatterjee et al, 2001;Song et al, 2003;Galligan et al, 2005;Longley et al, 2006;Abedini et al, 2008), or Histone deacetylase (HDAC) inhibitors (such as suberoylanilidehydroxamic acid (SAHA, vorinostat), Depsipeptide, Trichostatin A, Valproic acid, MS-275 (entinostat)) (Pathil et al, 2006;Park et al, 2009;Rao-Bindal et al, 2013;Riley et al, 2013;Feng et al, 2014). One of the most promising HDAC inhibitors is SAHA, which causes degradation of c-FLIP variants via an ubiquitin/proteasome-dependent Itch/AIP4-independent mechanism (Yerbes and LopezRivas, 2012).…”

Section: Targeting C-flipmentioning

confidence: 99%

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Goldar¹,

Khaniani²,

Derakhshan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

490

338

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Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

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“…12,30,[32][33][34] In some malignant cells including EBVinfected Burkitt lymphoma, the relative levels of caspase 8 and c-FLIP were reported to determine susceptibility to Fas-mediated apoptosis. 10,35 Moreover, the downregulation of c-FLIP sensitized Hodgkin lymphoma cells, 14 hepatocellular carcinoma cells, 12 Jurkat T-cell lymphoma cells, 11 osteosarcoma cells, 13 and endothelial cells 36 to Fas-mediated apoptosis. c-FLIP is a short-lived protein, and thus the prototypic method used to downregulate c-FLIP is protein synthesis inhibition by CHX.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Abnormally high c-FLIP expression has been reported in many malignancies, and it has also been reported that the downregulation of c-FLIP sensitizes variable tumor cells to Fas-mediated apoptosis. [11][12][13][14] NKTL is a neoplasm that originates from natural killer (NK) cells and rarely from cytotoxic T cells. Epstein-Barr virus (EBV) is latently infected in nearly all NKTLs irrespective of ethnic or geographic origin, and thus EBV is believed to be an important pathogenic component.…”

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confidence: 99%

Resistance to Fas-mediated apoptosis is restored by cycloheximide through the downregulation of cellular FLIPL in NK/T-cell lymphoma

Jeon

Kim

Park

et al. 2005

Laboratory Investigation

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Extranodal NK/T-cell lymphoma (NKTL), nasal type, is a highly aggressive neoplasm and is strongly associated with Epstein-Barr virus (EBV). In this study, we demonstrate that EBV-positive NKTL cell lines, namely, Hank-1, NK-YS, and NK-L, are resistant to Fas-mediated apoptosis induced by anti-Fas antibodies despite high levels of Fas surface expression and no mutation in the Fas gene. Fas stimulation of Hank-1 and NK-YS cells showed little processing of caspase 8, caspase 3, or bid, although the proximal signaling molecules of the deathinducing signaling complex, namely, Fas, Fas-associated protein with a death domain, caspase 8, and bid were present in these cells. Consistent with previous reports on the hypermethylation of death associated protein (DAP) kinase in NKTLs, the promoter of DAP kinase was methylated and its mRNA not detected in Hank-1 cells. However, the restoration of DAP kinase expression by 5-aza-2 0 -deoxycytidine did not sensitize Hank-1 to Fasmediated apoptosis, indicating that DAP kinase deficiency does not contribute to resistance to Fas-mediated apoptosis. Since etoposide-induced apoptosis involved caspase 3 activation in Hank-1 and NK-YS cells, the caspase 3-dependent apoptotic machinery appears to be intact. Interestingly, cotreatment of Hank-1 with cycloheximide, a protein synthesis inhibitor, markedly sensitized cells to Fas-mediated apoptosis along with caspase 8 activation and c-FLIP L (cellular FLICE inhibitory protein long form) downregulation. Moreover, immunohistochemistry on paraffin-embedded tissue revealed c-FLIP expression in 39% (14 of 36) of NKTL patients. Taken together, these findings indicate that c-FLIP L -mediated resistance to Fas contributes to the development and progression of NKTLs. This study also suggests that agents capable of downregulating c-FLIP L could be used to treat NKTL. Laboratory Investigation (2005) 85, 874-884.

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Cisplatin (CDDP) sensitizes human osteosarcoma cell to Fas/CD95-mediated apoptosis by down-regulating FLIP-L expression

Cited by 69 publications

References 28 publications

FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells

FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Resistance to Fas-mediated apoptosis is restored by cycloheximide through the downregulation of cellular FLIPL in NK/T-cell lymphoma

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