Sensitization of human colon cancer cells to trail-mediated apoptosis

Hernandez, Ambrosio; Schwartz, Stephanie A.; Wang, QingDing; Evers, B. Mark

doi:10.1016/s0016-5085(00)86250-2

Cited by 8 publications

(9 citation statements)

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“…Human melanoma and colon cancer cells, resistant to TRAIL, were noted to have increased FLIP protein levels. A reduction of FLIP levels was associated with an increased sensitivity to TRAIL-mediated cell death (Zhang et al, 2000;Hernandez et al, 2001). However in another study, no correlation between FLIP levels and TRAIL sensitivity was observed for colon cancer cell lines (Lacour et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

Geelen

Vries

et al. 2003

Br J Cancer

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L) are potent inducers of apoptosis in various tumour cell types. Death receptors DR4 and DR5 can induce and decoy receptors DcR1 and DcR2 can inhibit TRAILmediated apoptosis. The study aim was to investigate whether anticancer agents can modulate similarly TRAIL-receptor and CD95 membrane expression and TRAIL and CD95L sensitivity.Three colon carcinoma cell lines (Caco-2, Colo320 and SW948) were treated with 5-fluorouracil (5-FU), cisplatin or interferon-g. TRAIL-receptor and CD95 membrane expression was determined flow cytometrically. Sensitivity to TRAIL or CD95L agonistic anti-CD95 antibody was determined with cytotoxicity and apoptosis assays. SW948 showed highest TRAIL sensitivity. The protein synthesis inhibitor cycloheximide decreased FLICE-like inhibitory protein levels in all cell lines, and the TRAIL-resistant cell lines Caco-2 and Colo320 became sensitive for TRAIL. Exposure of the cell lines to 5-FU, cisplatin and interferon-g left TRAIL-receptor membrane expression and TRAIL sensitivity unaffected. CD95 membrane expression and anti-CD95 sensitivity was, however, modulated by the same drugs in all lines. Cisplatin and interferon-g raised CD95 membrane levels 6 -8-fold, interferon-g also increased anti-CD95 sensitivity. These results indicate that the CD95 and TRAIL pathways use different mechanisms to respond to various anticancer agents. Induced CD95 membrane upregulation was associated with increased anti-CD95 sensitivity, whereas no upregulation of TRAIL-receptor membrane expression or TRAIL sensitisation could be established. For optimal use of TRAIL-mediated apoptosis for cancer therapy in certain tumours, downregulation of intracellular inhibiting factors may be required.

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Section: Discussionmentioning

confidence: 99%

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

Geelen

Vries

et al. 2003

Br J Cancer

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“…In addition, they showed that SAHA disrupts the FLIP/ Ku70 complex via increasing the acetylation of Ku70, which consequently triggers FLIP polyubiquitination and degradation by the proteasome (Kerr et al, 2012). C-FLIP has been demonstrated to be down-regulated by several compounds such as actinomycin D (Hernandez et al, 2001), cycloheximide (Kaminskyy et al, 2013), and anisomycin (Mawji et al, 2007a); the first is an RNA synthesis inhibitor, and the second and third are protein synthesis inhibitors. Moreover, protease inhibitors such as Bortezomib (PS-34) have been extensively studied and shown to have the ability to reduce c-FLIP in diverse cell lines (Koschny et al, 2007;Perez et al, 2010).…”

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

486

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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“…c-FLIP has homology to caspase-8 and -10 but lacks their protease activity and thereby prevents the activation of procaspase-8 and potently inhibits apoptosis mediated by death receptors (1,2). As an important antiapoptotic protein, c-FLIP has been shown to be overexpressed in human tumor cells, including colorectal carcinoma, hepatocellular carcinoma, pancreatic carcinoma, and prostate carcinoma (3)(4)(5)(6)(7). Dysregulation of c-FLIP expression has been proven to be one of the major determinants of the resistance to death ligands such as FasL and TRAIL, which suggests that targeting c-FLIP is an appealing way to anticancer therapy (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of c-FLIP expression by miR-512-3p contributes to Taxol-induced apoptosis in hepatocellular carcinoma cells

Chen

2010

Oncol Rep

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Abstract. Dysregulation of the antiapoptotic protein cellular FLICE-like inhibitory protein (c-FLIP) has been proven to be associated with tumorigenesis and progress of most human cancers. However, its aberrant expression is poorly elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in tumorigenesis through negatively regulating gene expression. Our study disclosed that c-FLIP was overexpressed in HepG2 hepatocellular carcinoma cells and downregulation of c-FLIP enhanced Taxol-induced apoptosis. Taxol induction significantly decreased the protein level of c-FLIP. While no decrease in c-FLIP mRNA level was observed, indicating Taxol decreased c-FLIP expression through a posttranscriptional mechanism. miR-512-3p was a predicted suppressor of c-FLIP and exhibited an opposite expression manner to c-FLIP before and after Taxol induction. Luciferase report assay demonstrated miR-512-3p negatively regulated c-FLIP expression via a conserved miRNA-binding site in 3' untranslated region (3'UTR) of c-FLIP. The decrease of c-FLIP protein due to transfection of miR-512-3p further validated the inhibitory effect of miR-512-3p on c-FLIP. Additional transfection of miR-512-3p remarkably promoted Taxol-induced apoptosis, confirming its involvement in apoptosis. In summary, our study disclosed a novel regulatory mechanism that down-regulation of c-FLIP by miR-512-3p contributed to Taxol-induced apoptosis. Importantly, the pivotal role of miR-512-3p in determining c-FLIP abundance helps to broaden the implications for cancer therapy by developing small molecules to directly target c-FLIP at mRNA level.

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Sensitization of human colon cancer cells to trail-mediated apoptosis

Cited by 8 publications

References 0 publications

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Inhibition of c-FLIP expression by miR-512-3p contributes to Taxol-induced apoptosis in hepatocellular carcinoma cells

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