Biology subjects

Ausloos, E.

Publications and source records attributed to Ausloos, E..

2 recordsLinked to original sources

bioRxiv2026

A druggable ATP13A3-antizyme switch controls adaptive polyamine uptake in cancer

Cellular polyamine depletion is a promising anticancer strategy, but compensatory polyamine uptake limits efficacy when synthesis is blocked by DFMO (difluoromethylornithine), a clinically approved inhibitor of ornithine decarboxylase. The transporter and feedback mechanism driving this adaptive response have remained unclear. Despite their similar biochemical properties, we identify ATP13A3, rather than ATP13A2, as the principal DFMO-responsive polyamine importer, suggesting that these isoforms regulate distinct polyamine fluxes. Mechanistically, the polyamine sensor antizyme not only restrains polyamine biosynthesis but also selectively inhibits ATP13A3-mediated uptake, a brake that is relieved upon DFMO treatment. This regulatory circuit exposes distinct polyamine-acquisition states across cancers, defining synthesis- and/or uptake-biased subtypes that can shift during disease progression. Melanoma metastasis and vemurafenib resistance evolve toward increased ATP13A3-dependent uptake. The polyamine uptake branch controlled by ATP13A3-antizyme regulation can be pharmacologically blocked by AMXT 1501, which directly inhibits ATP13A3. Together, our findings explain DFMO adaptation through ATP13A3-antizyme control and establish ATP13A3 as a targetable node for polyamine depletion strategies in multiple cancers, supporting ongoing clinical evaluation of combined DFMO/AMXT 1501 therapy.

cell biology↗

bioRxiv2023

ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7

Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). So far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether upregulation of candidate polyamine transporters of the P5B- transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells present elevated expression of a previously uncharacterized P5B-ATPase ATP13A4, which is responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells are more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, overexpression of ATP13A4 WT in MCF10A cells induces a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labelled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we establish ATP13A4 as a new polyamine transporter in the human PTS and show that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.

cell biology↗