Prognostic Impact of p62 Expression in Cutaneous Malignant Melanoma

Ellis, Robert; Horswell, Stuart; Ness, Tom; Lumsdon, J; Tooze, Sharon A.; Kirkham, N.; Armstrong, Jane L.; Lovat, Penny E.

doi:10.1038/jid.2013.497

Cited by 39 publications

(39 citation statements)

References 8 publications

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“…Thus, based on our past and current studies as well as others, it can be proposed that cytoprotective autophagy represents a mechanism of danger-signalling suppression in dying melanoma cells [67]. Due to melanomas' addiction to autophagy [22], especially in late stage metastatic disease [22,68], autophagy inhibition appears to be a viable strategy to increase MEK-inhibition-induced cell death associated with danger-signalling, thus advocating the need for autophagy inhibitor-based trials in a BRAF V600E related context. Moreover, the recent clinical finding that single agent targeting of MEK was insufficient to elicit a durable response in patients, may further implicate the need for combination therapy.…”

Section: Discussionmentioning

confidence: 95%

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells

Martin

Dudek-Perić

Maes

et al. 2015

Biochemical Pharmacology

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Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma.

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Section: Discussionmentioning

confidence: 95%

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells

Martin

Dudek-Perić

Maes

et al. 2015

Biochemical Pharmacology

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“…Thus far, little is known about to what extent autophagy plays a role in nevus > melanoma progression and in melanoma in its early versus advanced stages. However, it has been reported that RGP, VGP, and in particular MGP melanomas express significantly lower levels of LC3 than nevi (30) and that median p62/ SQSTM1 expression levels are lower in American Joint Committee on Cancer (AJCC) stage III/IV than in AJCC stage I/II melanomas (31). This is in concordance with our finding that the two MGP melanoma cell lines, WM983-B and SK-MEL-5, that had received DMSO only, showed an LC3-positive phagosome signal in less than 1% of the cells and that the level of p62/ SQSTM1 expression in the DMSO-treated WM983-B cells was low.…”

Section: Discussionmentioning

confidence: 99%

Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Turriani

Lázaro

Ryazanov

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell's survival. melanoma | Parkinson's disease | α-synuclein | oligomer modulator treatment | autophagy

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“…Conversely, decreased levels of p62 reflect active autophagy, as observed in advanced stage melanomas where autophagy is commonly reactivated to enhance tumor survival (Figure 1A). Data from our lab have further defined p62 expression as a prognostic biomarker for melanoma where a stepwise increase in expression is observed in early AJCC stage melanomas (increased above basal levels in benign nevi and reflecting deregulated autophagy) but which is subsequently decreased in advanced metastatic tumors, consistent with the reactivation of autophagy and its paradoxical role in cancer [Figures 1B,C; (26)]. Furthermore, univariate analysis showed a significantly increased risk of metastasis in AJCC stage II tumors with low p62 expression (<20% median p62 expression) compared to those with high expression (>20% p62 expression) [Figure 1D; (26)].…”

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confidence: 81%

“…Each point represents the mean % of p62 positive cells. Horizontal lines representing median p62 expression levels indicate an increase in median p62 expression levels between benign nevi and AJCC stage I or II melanomas and a relative decrease in expression in advanced AJCC stages III and IV tumors (Kruskal–Wallis P < 0.0001) (26). (C) Photomicrographs of immunohistochemical p62 expression and mean % in a melanocytic nevus or an eventual AJCC stage I, II, or IV melanoma.…”

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confidence: 99%

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Prognostic Impact of Autophagy Biomarkers for Cutaneous Melanoma

2016

Self Cite

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Prognosis and survival for malignant melanoma is highly dependent on early diagnosis and treatment. While the American Joint Committee on Cancer (AJCC) criterion provides a means of staging melanomas and guiding treatment approaches, it is unable to identify the risk of disease progression of early stage tumors or provide reliable stratification for novel adjuvant therapies. The demand for credible prognostic/companion biomarkers able to identify high-risk melanoma subgroups as well as guide more effective personalized/precision-based therapy is therefore of paramount importance. Autophagy, the principle lysosomal-mediated process for the degradation/recycling of cellular debris, is a hot topic in cancer medicine, and observations of its deregulation in melanoma have brought its potential as a prognostic biomarker to the forefront of current research. Key regulatory proteins, including Atg8/microtubule-associated light chain 3 (LC3) and BECN1 (Beclin 1), have been proposed as potential prognostic biomarkers. However, given the dynamic nature of autophagy, their expression in vitro does not translate to their use as a prognostic biomarker for melanoma in vivo. We have recently identified the expression levels of Sequestosome1/SQSTM1 (p62) and activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) as novel independent prognostic biomarkers for early stage melanomas. While increasing followed by subsequent decreasing levels of p62 expression reflects the paradoxical role of autophagy in melanoma, expression levels additionally define a novel prognostic biomarker for AJCC stage II tumors. Conversely, loss of AMBRA1 in the epidermis overlying primary melanomas defines a novel prognostic biomarker for AJCC stage I tumors. Collectively, the definition of AMBRA1 and p62 as prognostic biomarkers for early stage melanomas provides novel and accurate means through which to identify tumors at risk of disease progression, facilitating earlier patient therapeutic intervention and stratification tools for novel personalized therapeutic approaches to improve clinical outcome.

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Prognostic Impact of p62 Expression in Cutaneous Malignant Melanoma

Cited by 39 publications

References 8 publications

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells

Treatment with diphenyl–pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death

Prognostic Impact of Autophagy Biomarkers for Cutaneous Melanoma

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