Alterations of Fas (Apo-1/CD95) Gene in Cutaneous Malignant Melanoma

Shin, Min Sun; Park, Won Sang; Kim, Su Young; Kim, Ho Sik; Kang, Seok Jin; Song, Kye Yong; Park, Jik Young; Dong, Seung Myung; Pi, Jae Ho; Oh, Ro Ra; Lee, Jung Young; Yoo, Nam Jin; Lee, Sug Hyung

doi:10.1016/s0002-9440(10)65434-x

Cited by 123 publications

(76 citation statements)

References 38 publications

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“…Fas mutations resulting in loss of function imply that Fas may act as a tumor suppressor gene. This hypothesis is supported by recent findings of genomic instability as detected by LOH in the Fas promotor region in solid tumors (Lee et al, 1999a(Lee et al, , 1999bShin et al, 1999), but is in contrast to results with MALT-type lymphoma, because we could not find LOH in any of the cases investigated. However, hypermutation and ongoing mutations of MALT-type lymphoma antigen receptors support the notion that clonal growth of malignant B cells occurred during or after the germinal center development (Hallas et al, 1998;Qin et al, 1997).…”

Section: Loss Of Fas Function In Malt-lymphomasupporting

confidence: 89%

Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

Seeberger

Starostik

Schwarz

et al. 2001

Laboratory Investigation

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SUMMARY:Fas (CD95, APO-1) mutations were found in autoimmune diseases and some lymphomas, suggesting impairment of Fas-mediated cell death signaling that may cause tumor development. Because mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells recognize autoantigens and proliferate in response to antigen and T cell-mediated signals, it is suggestive that autoreactive B cell lymphoma precursor cells may have escaped the Fas-mediated checkpoint that normally operates in healthy individuals. Using different biochemical, molecular, and functional approaches, we analyzed the Fas signaling in malignant B cells from seven MALT-type lymphomas that were additionally characterized for the t(11;18)(q21;q21) and four gastric diffuse large B cell lymphomas (DLBL). All DLBLs and three of seven MALT-type lymphomas were resistant to Fas-mediated apoptosis in vitro. Moreover, four of five MALT-type lymphomas analyzed and one of three DLBLs analyzed showed mutations in Fas mRNA transcripts but no loss of heterozygosity in the Fas promotor region. Alternative mechanisms of resistance to apoptosis, such as decreased expression of Fas or production of soluble Fas were not operative. Therefore, it is suggestive that a subgroup of MALT-type lymphoma B cells, irrespective of t(11;18)(q21;q21), escape the censoring Fas pathway by mutating and inactivating Fas. This identifies a key regulatory step in early MALT-type lymphomagenesis. (Lab Invest 2001, 81:977-986).M arginal zone B cell lymphomas of mucosaassociated lymphoid tissue (MALT)-type are neoplastic counterparts of normal memory B cells (Harris et al, 1994). The development from naive to memory B cells is closely accompanied and regulated by T cells through Fas/FasL interaction (Nagata, 1997;Suda et al, 1993) taking place in the germinal centers of follicles and leading either to deletion of autoantigen-recognizing B cells or to further differentiation into memory B cells resident in the marginal zone of the follicle (Goodnow, 1996;Rathmell et al, 1996) and plasma cells. Therefore, disruption of the Fas/FasL apoptotic pathway is associated with lymphoproliferative and autoimmune disorders as demonstrated in mice carrying lymphoproliferation (lpr) or generalized lymphoproliferative disease (gld) mutations affecting the genes for Fas and FasL, respectively (Takahashi et al, 1994;Watanabe-Fukunaga et al, 1992), or in humans carrying inherited mutations in the Fas gene leading to autoimmune lymphoproliferative syndrome (Bettinardi et al, 1997;Fisher et al, 1995;Rieux Laucat et al, 1995;Sneller et al, 1997). Because autoantigen receptors and marginal zone B cell expansions are characteristic features of MALT-type lymphoma , we searched for a link between tumor development and functionality of the Fas/FasL apoptotic pathway. In addition, the translocation t(11;18)(q21;q21) is the most characteristic chromosomal aberration in extranodal MALT-type lymphoma and may interfere with the regulation of apoptosis. In recent studies, the gene for the human inhibitor of apoptosis protein...

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Section: Loss Of Fas Function In Malt-lymphomasupporting

confidence: 89%

Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

Seeberger

Starostik

Schwarz

et al. 2001

Laboratory Investigation

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“…In this study, we have shown that Mcl-1 protein, a member of the Bcl-2 antiapoptotic family, plays a major role in the resistance of melanoma cells toward Fas-mediated apoptosis. Several studies have shown that melanoma tumor cells express variable levels of Fas in vivo and in vitro but were found to be resistant to Fasinduced apoptosis (35,36), suggesting that additional mechanisms at the level of Fas-induced caspase activation are likely to contribute to the observed resistance. We show that Mcl-1 is constitutively expressed in resistant melanoma cell lines and its knockdown using siRNA sensitizes these cells toward Fasinduced apoptosis, whereas overexpression of Mcl-1 protects sensitive melanoma cell lines from Fas-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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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“…49,50 In addition, mutations in the death domain of CD95/Fas have been described for melanoma. 51 The role of soluble CD95 (sCD95) and sCD95L in the response of human melanoma to chemotherapy in vivo. 52 Patients with low clinical response to various drugs (cisplatin, recombinant IL-2 and IFN-␣) exhibited a significant increase of sCD95 and sCD95L in the plasma after drug treatment, whereas in the plasma of responders, no changes in sCD95/sCD95L levels were observed.…”

Section: Drug Resistance Via Modulation Of the Apoptotic Pathwaymentioning

confidence: 99%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

164

137

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Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/ extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.

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Alterations of Fas (Apo-1/CD95) Gene in Cutaneous Malignant Melanoma

Cited by 123 publications

References 38 publications

Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

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

Drug-resistance in human melanoma

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