Role of GDF15 in radiosensitivity of breast cancer cells

Schilling-Tóth, Boglárka; Sándor, Nikolett; Walter, Fruzsina R.; Bocsik, Alexandra; Sáfrány, Géza; Hegyesi, Hargita

doi:10.2478/s11535-014-0328-8

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…6I and J). GDF-15 is an important factor with immunosuppressive characteristics that supports prostate cancer cell growth (41,51), but it is also known to protect cancer cells against radiation-induced cell death (36), to mediate tumor-mediated anorexia and weight loss (50) as well as to sustain tumor neovascularization (37). These observations however do not exclude that PACE4 probably have other substrates contributing to the observed effects.…”

Section: Discussionmentioning

confidence: 99%

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PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

“…6A and B). GDF-15 is an important growth factor for prostate tumor progression and resistance to cytotoxic agents and radiotherapy in prostate cancer and other cancers (36)(37)(38)(39)(40)(41). Upon GDF-15 silencing (Fig.…”

Section: Identification Of Gdf-15 As a Specific Pace4 Substrate And Pmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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“…GDF15 and TGFB1 genes are members of transforming growth factor beta family, and encode multifunctional proteins associated with proliferation, differentiation, adhesion, and migration. Therapeutically, these genes are related to response of breast cancer cells to radiation, specifically inhibiting radiation-induced cell death and related cytotoxic action [50] and a direct association between promoter methylation and expression of these genes are reported [51]. In addition, integrated analysis showed GSTP1 and PALLD genes having low level gene expression as well as significantly higher methylation level of these gene promoters in luminal phenotype compared to the other two subtypes.…”

Section: Discussionmentioning

confidence: 99%

Subtype-specific CpG island shore methylation and mutation patterns in 30 breast cancer cell lines

et al. 2016

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BackgroundAberrant epigenetic modifications, including DNA methylation, are key regulators of gene activity in tumorigenesis. Breast cancer is a heterogeneous disease, and large-scale analyses indicate that tumor from normal and benign tissues, as well as molecular subtypes of breast cancer, can be distinguished based on their distinct genomic, transcriptomic, and epigenomic profiles. In this study, we used affinity-based methylation sequencing data in 30 breast cancer cell lines representing functionally distinct cancer subtypes to investigate methylation and mutation patterns at the whole genome level.ResultsOur analysis revealed significant differences in CpG island (CpGI) shore methylation and mutation patterns among breast cancer subtypes. In particular, the basal-like B type, a highly aggressive form of the disease, displayed distinct CpGI shore hypomethylation patterns that were significantly associated with downstream gene regulation. We determined that mutation rates at CpG sites were highly correlated with DNA methylation status and observed distinct mutation rates among the breast cancer subtypes. These findings were validated by using targeted bisulfite sequencing of differentially expressed genes (n=85) among the cell lines.ConclusionsOur results suggest that alterations in DNA methylation play critical roles in gene regulatory process as well as cytosine substitution rates at CpG sites in molecular subtypes of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0356-2) contains supplementary material, which is available to authorized users.

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