Expression of c-myc and bcl-2 in Primary and Advanced Cutaneous Melanoma

Utikal, Jochen; Leiter, Ulrike; Udart, Martin; Kaskel, Peter; Peter, Ralf Uwe; Krähn, Gertraud

doi:10.1081/cnv-120005904

Cited by 22 publications

(12 citation statements)

References 26 publications

(20 reference statements)

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“…However, the implication of Bcl-2 antiapoptotic proteins as melanoma progression factors is controversial. While some studies indicated that Bcl-2 and Bcl-X L gene expression increases with progression of malignant melanoma (Leiter et al, 2000;Utikal et al, 2002), others found that Bcl-2 and Bcl-X L did not correlate to progression of the disease (Gradilone et al, 2003). In the PI3K/AKT/PTEN survival pathway, AKT has been found to be constitutively activated in melanoma, which leads to upregulation of NFkB and tumour progression (Dhawan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Reduced Apaf-1 expression in human cutaneous melanomas

et al. 2004

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Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio-and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15 -20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (w 2 ¼ 6.02, P ¼ 0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma.

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Section: Discussionmentioning

confidence: 99%

Reduced Apaf-1 expression in human cutaneous melanomas

et al. 2004

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“…From both in vitro and in vivo melanoma model systems, several lines of evidence suggest that BCL-2 over-expression correlates with a malignant phenotype and a higher metastatic potential (Grover and Wilson, 1996; Takaoka et al, 1997; Xie et al, 1997; Leiter et al, 2000; Utikal et al, 2002; Zhang and Rosdahl, 2006). This seems logical, as a cell expressing more anti-apoptotic proteins should resist apoptosis despite cues to die following events from benign status to malignancy and metastasis.…”

Section: Melanoma and The Bcl-2 Familymentioning

confidence: 99%

Born to be Alive: A Role for the BCL-2 Family in Melanoma Tumor Cell Survival, Apoptosis, and Treatment

et al. 2011

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The global incidence of melanoma has dramatically increased during the recent decades, yet the advancement of primary and adjuvant therapies has not kept a similar pace. The development of melanoma is often centered on cellular signaling that hyper-activates survival pathways, while inducing a concomitant blockade to cell death. Aberrations in cell death signaling not only promote tumor survival and enhanced metastatic potential, but also create resistance to anti-tumor strategies. Chemotherapeutic agents target melanoma tumor cells by inducing a form of cell death called apoptosis, which is governed by the BCL-2 family of proteins. The BCL-2 family is comprised of anti-apoptotic proteins (e.g., BCL-2, BCL-xL, and MCL-1) and pro-apoptotic proteins (e.g., BAK, BAX, and BIM), and their coordinated regulation and function are essential for optimal responses to chemotherapeutics. Here we will discuss what is currently known about the mechanisms of BCL-2 family function with a focus on the signaling pathways that maintain melanoma tumor cell survival. Importantly, we will critically evaluate the literature regarding how chemotherapeutic strategies directly impact on BCL-2 family function and offer several suggestions for future regimens to target melanoma and enhance patient survival.

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“…Nevirapine treatment induced similar changes in TVM-A12 primary cells derived from melanoma ( Figure cultures treated with DMSO only, or nevirapine or efavirenz for four cycles. In A-375 melanoma cells, we focussed on a set of four genes: the E-cadherin gene, involved in cell-cell adhesion and expressed in differentiated but not in tumor cells (Hsu et al, 2000); and the c-myc, bcl-2 (Utikal et al, 2002) and cyclin D1 (Sauter et al, 2002) genes, which are directly implicated in melanoma cell proliferation and tumor growth. Results in Figure 4a indicate that the E-cadherin gene is markedly upregulated, whereas c-myc, bcl-2 and ccnd1 genes are downregulated, in RT-inhibited A-375 cultures compared to controls.…”

Section: Nevirapine Induces Morphological Differentiation and Modulatmentioning

confidence: 99%

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

et al. 2005

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Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.

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Expression of c-myc and bcl-2 in Primary and Advanced Cutaneous Melanoma

Cited by 22 publications

References 26 publications

Reduced Apaf-1 expression in human cutaneous melanomas

Reduced Apaf-1 expression in human cutaneous melanomas

Born to be Alive: A Role for the BCL-2 Family in Melanoma Tumor Cell Survival, Apoptosis, and Treatment

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

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