Biology subjects

Strauss, R.

Publications and source records attributed to Strauss, R..

3 recordsLinked to original sources

bioRxiv2025

Caspase-8 is a novel modulator of Homologous Recombination Repair in response to ionizing radiations

Caspase-8 is a cysteine protease historically regarded as anti-neoplastic protein, thanks to its role in apoptosis. However, Caspase-8 expression is retained or even enhanced in several tumors, including glioblastoma (GBM), where it plays pro-tumor functions. We previously reported that it is a negative prognostic factor and contributes to resistance against DNA damaging agents, such as ionizing radiations (IR) and Temozolomide, commonly used in standard GBM treatment. We therefore investigated whether Caspase-8 may sustain DNA repair pathways proficiency in GBM. Here we uncover a novel role of Caspase-8 as promoter of the Homologous Recombination Repair (HRR). Importantly, IR promote Caspase-8 transient nuclear translocation and its recruitment to the chromatin. Moreover, Caspase-8 sustains the expression and the recruitment to the chromatin upon IR of RAD51 and CtIP, two key players of the HRR. Consistently, we identify a synthetically lethal interaction between Caspase-8 and PARP inhibition, that may ameliorate GBM response to IR. Remarkably, by using Caspase-8-/- murine embryo fibroblasts and a Drosophila melanogaster Caspase-8 mutant, we demonstrate that Caspase-8 plays an evolutionary conserved role in DNA repair. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/656091v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1016001org.highwire.dtl.DTLVardef@145ed73org.highwire.dtl.DTLVardef@1e847d5org.highwire.dtl.DTLVardef@c417e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Glutamine-addiction in cisplatin resistant cancer cells is mediated by SLC7A11 and can be targeted with asparaginase therapy

Linking disease phenotypes with molecular targets is key to the rational design of treatment interventions. Resistance to the chemotherapeutic cisplatin is one of the major factors limiting the clinical utility of this therapy, which is central to the treatment of a variety of solid malignancies. In this study, we couple the upregulation of a chemoresistant factor, the glutamate-cystine antiporter SLC7A11, with the addiction of cisplatin-resistant cancer cells to extracellular glutamine. In doing so, we thus provide a putative biomarker for this acquired metabolic dependency of chemoresistance. Subsequently, we evaluate various therapeutic strategies to selectively kill SLC7A11high cisplatin-resistant cancer cells, identifying cross-resistance to ferroptosis-inducing compounds and hypersensitivity to glutaminase inhibitor CB-839. We identify enzymatic depletion of extracellular glutamine using the long-standing anti-leukemic therapy asparaginase (ASNase), which possesses glutaminase activity, as a potential approach, and show this can be successfully combined with cisplatin in cell models. In summary, this study mechanistically links an acquired metabolic dependency of chemoresistant cancer cells with a putative biomarker and provides a potentially actionable strategy to target these drug resistant cells warranting further investigation.

cancer biology↗

bioRxiv2023

Biological aging of two innate behaviors of Drosophila melanogaster: escape climbing versus courtship learning and memory

Motor and cognitive aging can severely affect life quality of elderly people and burden health care systems. In search for diagnostic behavioral biomarkers, it has been suggested that walking speed can predict forms of cognitive decline, but in humans, it remains challenging to separate the effects of biological aging and lifestyle. We examined a possible association of motor and cognitive decline in Drosophila, a genetic model organism of healthy aging. Long term courtship memory is present in young flies but absent already during mid life (4-8 weeks). By contrast, courtship learning index and short term memory (STM) are surprisingly robust and remain stable through mid (4-8 weeks) and healthy late life (>8 weeks), until courtship performance collapses suddenly at [~]4.5 days prior to death. By contrast, climbing speed declines gradually during late life (>8 weeks). The collapse of courtship performance and short term memory close to the end of life are not related to the gradual late life decline in climbing speed. Thus, during healthy aging in Drosophila, climbing and courtship motor behaviors decline differentially, unlikely share a common cause, and motor and cognitive performance decline are not closely associated to each other.

animal behavior and cognition↗