Expression of c‐FLIP is primarily detected in diffuse large B‐cell lymphoma and Hodgkin’s lymphoma and correlates with lack of caspase 8 activation

Houdt, Inge S. van; Muris, J J; Hesselink, Albertus T.; Kramer, Duco; Cillessen, Saskia A.G.M.; Moesbergen, Laura M; Vos, Wim; Hooijberg, Erik; Meijer, Chris J.L.M.; Kummer, J. Alain; Oudejans, Joost J.

doi:10.1111/j.1365-2559.2007.02882.x

Cited by 12 publications

(13 citation statements)

References 30 publications

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“…1,2 Moreover, changes in c-FLIP protein levels have been described in several B-cell malignancies. 8,[15][16][17][18][19] However, the functions of the different c-FLIP isoforms, in particular c-FLIP R , are yet not fully understood. For the 2 short isoforms, c-FLIP S and c-FLIP R , solely anti-apoptotic functions have been described so far, whereas the role of c-FLIP L is more controversial.…”

Section: Introductionmentioning

confidence: 99%

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein

Ueffing

Singh

Christians³

et al. 2009

Blood

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Section: Introductionmentioning

confidence: 99%

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein

Ueffing

Singh

Christians³

et al. 2009

Blood

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“…TRAIL usually induces apoptosis in tumor cells via the TRAIL-Rassociated DISC. However, in HRS cells, apoptosis induction via TRAIL-R-associated caspase-8 is prevented by the strong c-FLIP expression (44,45), and in cancer cells resistant toward TRAIL-induced apoptosis, TRAIL increased survival in a NF-kB-dependent fashion (46). It is thus conceivable that in HRS cell lines, the lestaurtinib induced increases in TRAIL expression also contribute to NF-kB activation.…”

Section: Discussionmentioning

confidence: 97%

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Holz

Janning

Renné

et al. 2013

Molecular Cancer Therapeutics

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Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) a, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3-independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRa, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal-regulated kinase 1/2 and the alternative NF-kB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-kB activation as a potential novel mechanism of resistance toward TKIs.

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“…Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not [130].…”

Section: Malignant Melanomamentioning

confidence: 95%

“…or expressing proteins interfering with cytotoxic lymphocyte-induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9) [130]. Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not [130].…”

Section: Malignant Melanomamentioning

confidence: 99%

Apoptosis in Physiological and Pathological Skin: Implications for Therapy

Boehm

2006

CMM

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Apoptosis is an inducible suicide program that occurs in all phases of multicellular as well as in protozoa life and gains more and more importance in all medical disciplines. It is required for normal ontogenesis, organ and tissue remodeling, function of the immune system, prevention of inappropriate cellular proliferation and of survival of inappropriate mutations. Thereby apoptosis represents the key event which guarantees differentiation and maintenance of homeostasis. Terminal differentiation seems to be a special form of apoptosis. Dysregulated apoptosis is associated with various pathological conditions, including inflammation, and cancer. Acanthosis, the hallmark of psoriatic skin, is an example for diminished epidermal apoptosis. Defects in termination of inflammatory reactions occur in atopic dermatitis. Lupus erythematosus may arise due to disturbed apoptosis on several check points of the apoptosis cascade. Experimental evidence suggests a role for Bcl-2 and CD95L in the inhibition of programmed cell death in UV-induced skin cancer or malignant melanoma cells. Thus, it leads to survival of malignant cell clones. The slow growth of basal cell carcinomas is due to an increased apoptosis to mitosis ratio. Spontaneous regression of tumors is associated with increased apoptotic rates. Malignant melanoma cells characteristically show different anti-apoptotic strategies which underscore its aggressive behavior and its refractory towards classic therapeutic regimens. Additionally, induction of apoptosis in tumor infiltrating immune cells seems to be a strategy by which the tumor escapes from an immunological attack (tumor counter-attack). Since apoptosis is either absent or altered under pathological conditions therapeutic procedures should correct this. Established therapies like dithranol, vitanin-D3 analogs, low-dose methotrexate, induce apoptosis. Future treatment regimens like vaccine and gene therapy are designed to selectively induce apoptosis. Therefore, pharmacological agents and therapeutic strategies interfering with disrupted apoptosis regulation could improve the therapeutic arsenal in the future.

show abstract

Expression of c‐FLIP is primarily detected in diffuse large B‐cell lymphoma and Hodgkin’s lymphoma and correlates with lack of caspase 8 activation

Cited by 12 publications

References 30 publications

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Apoptosis in Physiological and Pathological Skin: Implications for Therapy

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