Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

MacFarlane, Marion; Harper, Nicholas W.; Snowden, Roger T.; Dyer, Martin J. S.; Barnett, Georgina; Pringle, J. H.; Cohen, Gerald M.

doi:10.1038/sj.onc.1205853

Cited by 179 publications

(173 citation statements)

References 56 publications

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“…Therefore, enhanced activation of caspase-8 can be explained by the increased ratio of caspase-8 to cFLIP within the TRAIL DISC of tumour cells. 70 Efficient recruitment of caspase-8 to the DISC and its activation at this complex is decisive for TRAIL sensitivity. Notably, the described sensitisation mechanism for tumour cells does not apply for primary human hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

et al. 2004

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Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosisinducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC.

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Section: Discussionmentioning

confidence: 99%

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

et al. 2004

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“…5,8 Therefore, TRAIL is considered a promising tool for novel therapies. The receptors for TRAIL are constitutively expressed in several tumours, including B-CLL 9,10 ; however, in B-CLL, its use is limited due to the frequent resistance of the lymphocytes of these patients to TRAIL-induced cell death. 11 One of the causes of cell-death resistance could reside in altered expression of apoptosis inhibitory molecules belonging to the DEDcontaining protein family, such as c-FLIP and PED (also known as PED/PEA-15), 12 which includes procaspase 8, procaspase 10 and FADD.…”

mentioning

confidence: 99%

Selective inhibition of PED protein expression sensitizes B‐cell chronic lymphocytic leukaemia cells to TRAIL‐induced apoptosis

Garofalo

Romano

Quintavalle

et al. 2006

Intl Journal of Cancer

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B-cell chronic lymphocytic leukaemia (B-CLL) cells fail to undergo apoptosis. The mechanism underlying this resistance to cell death is still largely unknown. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells, and thus represents an attractive tool for the treatment of cancer. Unfortunately, lymphocytes from B-CLL patients are resistant to TRAIL-mediated apoptosis. Thus, we aimed to study the involvement of PED, a DED-family member with a broad antiapoptotic action, in this resistance. We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED. Treatment of B-CLL cells with specific PED antisense oligonucleotides, a protein synthesis inhibitor or HDAC inhibitors, induced a significant downregulation of PED and sensitized these cells to TRAIL-induced cell death. These findings suggest a direct involvement of PED in resistance to TRAIL-induced apoptosis in B-CLL. It also identifies this DED-family member as a potential therapeutic target for this form of leukaemia. ' 2006 Wiley-Liss, Inc.

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“…These antibodies have been validated for flow cytometric measurement of surface TRAIL expression (Zhang et al, 2000;MacFarlane et al, 2002). A total of 10 6 trypsinised colon cells (live) were incubated in blocking buffer (PBS containing 10% normal goat serum) for 30 min on ice to block nonspecific binding.…”

Section: Sds -Page -Western Blottingmentioning

confidence: 99%

“…To do this, flow cytometric analysis of antibody-labelled nonfixed cells was performed. The antibodies used to detect TRAIL receptors have been well characterised for efficient receptor binding by Griffith et al (1999) and for detection of cell surface TRAIL receptors by flow cytometry (Zhang et al, 2000;MacFarlane et al, 2002). TRAIL-R1 levels were low and similar in adenoma and carcinoma cell lines (Table 1).…”

Section: Cell Surface Receptor Expression Profiles Of Adenoma and Carmentioning

confidence: 99%

Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis

et al. 2005

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The death ligand TRAIL (Apo2L) has potential for cancer therapy, since tumour cells are thought to be more sensitive than normal cells. We investigated whether sensitivity to TRAIL increases during the adenoma to carcinoma transition of colorectal carcinogenesis. Under the same culture conditions, we compared the extent of TRAIL-induced apoptosis in four premalignant adenoma and three carcinoma cell lines. Although TRAIL induced some apoptosis in adenoma cultures, the carcinoma cell lines were significantly more sensitive (Po0.001). This finding was recapitulated in an in vitro model of tumour progression in which conversion of the adenoma cell line AA/C1 to a tumorigenic phenotype was associated with increased TRAIL sensitivity (Po0.001). Increased TRAIL sensitivity during colorectal carcinogenesis has been previously attributed to changes in the balance between TRAIL receptors TRAIL-R1 and -R2 and 'decoy' receptors TRAIL-R3 and -R4 during malignant progression. To address this, cell surface receptor expression was measured by flow cytometry. In summary, during colorectal carcinogenesis, there is a marked increase in sensitivity to TRAIL-induced apoptosis associated with progression from benign to malignant tumour that could be exploited for colon cancer therapy, but alterations in cell surface TRAIL receptor expression may not be the primary reason for this change.

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Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

Cited by 179 publications

References 56 publications

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs

Selective inhibition of PED protein expression sensitizes B‐cell chronic lymphocytic leukaemia cells to TRAIL‐induced apoptosis

Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis

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