Biology subjects

Soroka, Y.

Publications and source records attributed to Soroka, Y..

4 recordsLinked to original sources

bioRxiv2024

A Novel Cisplatin-Based Prodrug Inhibits Lysine Deacetylases, Suppresses Nucleotide Excision Repair, and Overcomes Resistance

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage, but drug resistance severely limits its efficacy and use. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcription regulation. The combination of cisplatin and KDAC inhibitors has shown promise in improving treatment efficacy. This improved efficacy has been attributed to increased drug sensitivity due to higher chromatin accessibility, however, this hypothesis has not been validated. In this study, we synthesized a novel Pt(IV) derivative, cct-[Pt(NH3)2Cl2(VPA)(PhB)] (cPVP), which combines cisplatin and two KDAC inhibitors, phenyl butyrate and valproic acid. This triple-action prodrug enabled the simultaneous targeting of multiple cancer-related pathways. Compared to cisplatin, cPVP exhibited significantly enhanced damage formation and cytotoxicity. High-resolution mapping of cisplatin damage and repair, however, does not attribute the enhanced damage sensitivity to chromatin accessibility, but rather to increased drug uptake and inhibition of nucleotide excision repair. Moreover, cPVP treatment increased survival in a mouse mesothelioma model, and prevented the development of resistance to both cisplatin and itself in cancer cells. Our findings shed new light on the effect of KDAC inhibition on cisplatin treatment, and suggest that cPVP could serve as a promising alternative to cisplatin in the clinic.

molecular biology↗

bioRxiv2024

Raffinose induces autophagy to promote plant growth

Plant growth is governed by the integration of environmental cues and nutritional status. Under stress conditions, growth is usually attenuated in favor of stress response, creating a trade-off between growth and stress. Autophagy is a vital process in eukaryotes, maintaining cellular balance by degrading and recycling cellular components. It is triggered by various nutrient-deprivation conditions and both biotic and abiotic stresses in plants. Surprisingly, over-expressing autophagy-related genes across multiple plant species resulted in increased plant size, yield, and stress resistance, posing autophagy as a regulator of the stress-growth balance. Yet, the molecular mechanisms governing its induction remain partially understood. In the current work, we identified raffinose-a plant-derived sugar known for its role in stress responses-as a novel plant autophagy inducer. Raffinose treatment resulted in increased biomass and yield in an autophagy-dependent manner in several plant species. We also show that raffinose activates autophagy through the SnRK1 kinase complex, independent of TOR signaling, and that raffinose treatment results in increased expression of ATG5 and ATG7. We also point to possible downstream candidates operating autophagy-related biomass accumulation. Our findings offer new perspectives on the role of autophagy in maintaining a balance between plant growth and stress responses, underscoring the significance of raffinose in its regulation. SIGNIFICANCE STATEMENTThe intricate balance between plant growth and stress responses is crucial for agricultural productivity, particularly as climate change intensifies environmental stressors such as drought and extreme temperatures. Usually, there is a trade-off between growth and stress response. Autophagy--a cellular recycling process essential for maintaining cellular homeostasis--plays a pivotal role in this balance. Yet, the molecular mechanisms modulating it are partially understood. Raffinose treatment enhances biomass and yields in various plant species by inducing autophagy. By elucidating the molecular mechanisms of raffinose-mediated autophagy induction, our findings provide valuable insights into potential strategies for enhancing plant resilience against climate-induced stress.

plant biology↗

bioRxiv2024

Autophagy at Crossroads: Modulating Responses to Combined Stresses, Unveiling Metabolic Shifts and Bacterial Dependencies

Plants face diverse stresses in natural environments, necessitating complex responses for survival. Abiotic and biotic stress responses are typically counteractive, posing challenges for breeding crops resilient to multiple stresses. Autophagy, a cellular transport process, plays a vital role in plant stress response, facilitating the degradation of cellular components and enabling nutrient recycling. Here, we asked what the role of autophagy is in combined abiotic (heat) and biotic (bacterial infection by Xanthomonas campestris pv. vesicatoria) stress. We introduce a conceptual framework based on assays monitoring autophagy activation, bacterial infection, and metabolic profiling. We observed that heat stress facilitates bacterial growth in an autophagy-dependent manner. Bacterial effectors facilitate this phenomenon. We also demonstrate the engagement of the autophagy-related 8 (ATG8) protein family members in stress-specific activation. Metabolic profiling highlights effector-dependent shifts in nutrient availability during stress, influencing bacterial performance. Our study challenges the assumption that combined stresses are simply the sum of individual responses as exemplified by activation of the autophagic pathway. Instead, it establishes autophagy as a link connecting environmental factors and plant-microbe interactions. Insights for our study can present a novel perspective for designing strategies to enhance crop resilience in the face of multifaceted challenges.

plant biology↗

bioRxiv2023

Autophagy in maternal tissues contributes to Arabidopsis thaliana seed development.

Seeds are an essential food source, providing nutrients for germination and early seedling growth. Degradation events in the seed and the mother plant accompany seed development. One degradation mechanism is autophagy, facilitating cellular component breakdown in the lytic organelle. Autophagy influences various aspects of plant physiology, specifically nutrient availability and remobilization, suggesting its involvement in source-sink interactions. During seed development, autophagy was shown to affect nutrient remobilization from mother plants and function in the embryo. Yet, these studies examined autophagy-knockout (atg mutant) plants, making it impossible to distinguish between the contribution of autophagy in the source (i.e., the mother plant) and the sink tissue (i.e., the embryo). To address this, we employed a novel approach to differentiate between autophagy in source and sink tissues. We investigated how autophagy in the maternal tissue affects seed development by performing reciprocal crosses between WT and atg mutant Arabidopsis thaliana plants. Although F1 seedlings possessed a functional autophagy mechanism, etiolated F1 plants from maternal atg mutants displayed reduced growth. This was attributed to altered protein but not lipid accumulation in the seeds, suggesting autophagy differentially regulates carbon and nitrogen remobilization. Surprisingly, F1 seeds of maternal atg mutants exhibited faster germination, resulting from different seed coat development. Our study emphasizes the significance of examining autophagy in a tissue-specific manner, revealing valuable insights into the interplay between different tissues during seed development. It sheds light on the tissue-specific functions of autophagy, offering potential for new research into the underlying mechanisms governing seed development and crop yield.

plant biology↗