Role of Apaf‐1, a key regulator of apoptosis, in melanoma progression and chemoresistance

Campioni, Mara; Santini, Daniele; Tonini, Giuseppe; Murace, Raffaele; Dragonetti, Emanuele; Spugnini, Enrico P.; Baldi, Alfonso

doi:10.1111/j.1600-0625.2005.00360.x

Cited by 58 publications

(42 citation statements)

References 75 publications

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“…Because most chemotherapeutics function by triggering the apoptotic pathway, apoptotic deregulation in melanoma cells plays an important role in promoting chemoresistance to these agents (4,36,46,47). The identity of PRAS40 as an Akt3 substrate promoting apoptotic deregulation and chemoresistance in melanoma cells is important for unraveling effective therapeutic strategies for melanoma patients.…”

Section: Discussionmentioning

confidence: 99%

PRAS40 Deregulates Apoptosis in Malignant Melanoma

Madhunapantula¹,

Sharma²,

2007

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Section: Discussionmentioning

confidence: 99%

PRAS40 Deregulates Apoptosis in Malignant Melanoma

Madhunapantula¹,

Sharma²,

2007

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“…In the gene array study, we found ApaF1 was elevated in the tumors in the WT mice compared to HFE mutant mice. APAF1 is a known regulator of apoptosis in cancers, including melanoma [26]. However, melanomas typically show downregulation of APAF1, so the lower APAF1 levels seen in H67D organisms, which possessed smaller tumors, was counterintuitive [27,28].…”

Section: Discussionmentioning

confidence: 99%

Host H67D Genotype Affects Tumor Growth in Mouse Melanoma

Weston¹,

Hund²,

Nixon³

et al. 2015

J Cancer Sci Ther

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BackgroundAlthough much clinical evidence exists to support a relationship between cancer and HFE genotype, the nature of this relationship and the mechanisms by which HFE function affect tumor progression are still unclear. HFE is an atypical MHC class I molecule that affects immune function [1,2] and HFE polymorphisms disrupt iron metabolism. It is already known that iron metabolism affects tumor progression [3]. Tumors require iron, and have increased ferritin and transferrin receptor 1 (TfR1) expression compared to normal tissue and stroma [4]. Clinically, we have previously reported that elevated ferritin, iron storage and transport protein, in serum are associated with poor prognosis in breast cancer [5]. Decreased levels of ferroportin in tumors, a protein responsible for iron export from cells, are linked to a more aggressive tumor phenotype in breast cancer [6]. Patients with hereditary hemochromatosis, who experience severe iron overload, showed a risk of liver cancer over two hundred times greater than matched controls. Hereditary hemochromatosis most often arises from mutations in the HFE gene and it has been commonly assumed that the cancers associated with the HFE mutation are related to excess iron accumulation [7].Two HFE variants are extremely common: H63D and C282Y. Of these, H63D is the more common form, seen in approximately 13.5% of people in the United States [8]. C282Y is the rarer form, seen in approximately 5.4% of the United States population [8]. Functionally, both of these result in a loss of normal HFE activity, although their mechanisms differ. H63D leads to a failure of the HFE protein to inhibit the binding of transferrin to the transferrin receptor, whereas C282Y leads to a failure of the HFE protein to reach the cell membrane at all [9]. In both cases, there is evidence that the presence of mutant protein affects cell biology in ways that are not modeled by HFE knockout mouse models. For example, H63D has been shown to increase ER stress, and C282Y has been shown to affect oxidative stress, mitochondrial membrane potential, and iron chelator response [10,11]. Therefore, the present study has chosen a mouse model exhibiting the H67D mutation, which is analogous to human H63D, to capture any effects of mutant protein expression. An investigation of C282Y would be equally valid, but H63D was chosen as a first step because of its comparatively high prevalence in human populations.Because HFE polymorphisms affect so many cell types, it is necessary to perform nuanced studies to understand the mechanisms by which HFE modulates tumor progression. To date, most work has focused on the manipulation of HFE in tumor cells [12] and in population based studies [13][14][15][16]. In the present study, we sought to test the central hypothesis that host HFE genotype modifies tumor progression. This approach contrasts with the majority of existing work because most available models vary the genotype of the cancer cell while using a normal or immunocompromised mouse host. Here, we used the syngene...

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“…Mature caspase-9 triggers a caspase cascade, necessary for apoptosis (29,30). APAF-1 was identified as a potential cellular target of FUS1, which is a novel tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

Promoter Methylation and mRNA Expression of APAF-1 Gene in Breast Cancer

Eskandari-Nasab

Hashemi

2016

Gene Cell Tissue

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Background: Apoptosis protease-activating factor-1 (APAF-1) is an important tumor suppressor gene, which plays a central function in DNA damage-induced apoptosis. The present study aimed to examine the epigenetic regulation of APAF-1 in breast cancer to gain a better understanding of tumor biology. Methods:The promoter methylation of APAF-1 gene was determined by methylation-specific polymerase chain reaction (MS-PCR) method, using 63 paraffin-embedded breast tumors and their corresponding normal tissues as the control tissue samples. Expression analysis was performed on all tissue samples, using quantitative PCR (qPCR) method.Results: Significant down-regulation was observed for APAF-1 expression among tumor tissues, compared to the control group (P = 0.011). APAF-1 promoter hypermethylation was more frequent in breast tumors in comparison with normal tissues (57% vs. 21%; P = 0.001) and was correlated with gene mRNA level (P < 0.05). Methylation level increased from the primary to the advanced stage of the disease (P = 0.001), which suggests the possible role of APAF-1 methylation in disease progression. Conclusions:Methylation is an important epigenetic factor which might contribute to the down-regulation of APAF-1 gene in breast tumor tissues.

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Role of Apaf‐1, a key regulator of apoptosis, in melanoma progression and chemoresistance

Cited by 58 publications

References 75 publications

PRAS40 Deregulates Apoptosis in Malignant Melanoma

PRAS40 Deregulates Apoptosis in Malignant Melanoma

Host H67D Genotype Affects Tumor Growth in Mouse Melanoma

Promoter Methylation and mRNA Expression of APAF-1 Gene in Breast Cancer

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