α-Synuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease

Israeli, Eitan; Yakunin, Eugenia; Zarbiv, Yonaton; Hacohen-Solovich, Amir; Kisos, Haya; Loeb, Virginie; Lichtenstein, Michal; Ben‐Gedalya, Tziona; Sabag, Ofra; Pikarsky, Eli; Lorberboum-Galski, Haya; Sharon, Ronit

doi:10.1371/journal.pone.0019622

Cited by 33 publications

(28 citation statements)

References 65 publications

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“…It has been reported that α-synuclein is expressed in melanoma (13) and that overexpressing it enhances the proliferation of B16 murine melanoma (14). However, scientific data regarding status and level of expression of the three major PD-related genes/proteins-α-synuclein/SNCA, LRRK2/PARK8, and parkin/PARK2-alongside one another in nevi and in early and advanced melanoma were not available.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…Some of these genes have also been found to have a role in the development, progression and dissemination of melanoma or other malignant processes. For example, increased expression of NRCAM and STMN1, potentiates proliferation and migration of melanoma cells, while SNCA, a gene primarily expressed in the brain, but also in various tumors including ovarian, colorectal and melanoma, is involved in tumorigenesis (45–48). …”

Section: Discussionmentioning

confidence: 99%

PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis

Jilaveanu

Parisi

Barr

et al. 2015

Clinical Cancer Research

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Purpose Approximately 40% of metastatic melanoma patients develop brain metastases. Our purpose was to identify genes aberrantly expressed in melanoma that might be associated with propensity for brain homing. Experimental Design We studied gene expression profiles in a cell line model of brain metastasis (cerebrotropic A375Br cells versus parental A375P cells) and compared them to profiles of patients who developed early brain metastases and who did not. A tissue microarray containing 169 metastatic melanoma cases with variable time to brain metastasis was constructed to further study marker expression by quantitative immunofluorescence. An in vitro model of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. Results PLEKHA5 was differentially expressed in both the A375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasis free survival. PLEKHA5 over-expression was not associated with other metastatic sites. Knock-down of PLEKHA5 decreases viability of A375Br cells, inhibits BBB transmigration and invasion in vitro. Similar results were found with YUMUL cells, cultured from a patient with overwhelming brain metastases. PLEKHA5 knock-down did not affect the viability of A375P cells. Conclusions PLEKHA5 expression in melanoma tumors was associated with early development of brain metastases. Inhibition of PLEKHA5 might decrease passage across the BBB and decrease proliferation and survival of melanoma cells both in the brain and in extra-cerebral sites.

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“…Intriguingly, PD patients have a higher risk of developing cancer [93], and in particular melanoma [94]. As a matter of fact, melanoma growth was increased in PD mice compared to wild-type mice [95,96]. Several hypotheses have been proposed to explain this finding.…”

Section: What Could Be the Relationship Between Glucosylceramide Gaumentioning

confidence: 99%

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Dubot

Astudillo

Therville

et al. 2020

Cancers

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The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

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α-Synuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease

Cited by 33 publications

References 65 publications

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

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

PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

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