Galactose-modified duocarmycin prodrugs as senolytics, bioRxiv, 2019-08-25

SUMMARYSenescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.

biorxiv cell-biology 0-100-users 2019

CD44 regulates epigenetic plasticity by mediating iron endocytosis, bioRxiv, 2019-07-09

SUMMARYCD44 is a transmembrane glycoprotein that is linked to various biological processes reliant on the epigenetic plasticity of cells, including development, inflammation, immune responses, wound healing and cancer progression. While thoroughly studied, functional regulatory roles of this so-called ‘cell surface marker’ remain elusive. Here, we report the discovery that CD44 mediates endocytosis of iron interacting with hyaluronates in tumorigenic cell lines and primary cancer cells. We found that this glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transition, unlike the canonical transferrin-dependent pathway. This transition is further characterized by molecular changes required for iron-catalyzed oxidative demethylation of the repressive histone mark H3K9me2 that governs the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron, demonstrating a positive feedback loop, which is in contrast to the negative regulation of transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This comprehensive study reveals an alternative iron uptake mechanism that prevails in the mesenchymal state of mammalian cells, illuminating a central role of iron as a rate-limiting regulator of epigenetic plasticity.

biorxiv cell-biology 0-100-users 2019

 

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