Biology subjects

Azzi, A.

Publications and source records attributed to Azzi, A..

5 recordsLinked to original sources

bioRxiv2026

SHIP2-SRC-β-catenin signaling axis sustains thymidylate synthase expression and promotes fluoropyrimidine resistance.

Fluoropyrimidine-based chemotherapies, including 5-fluorouracil (5-FU) and floxuridine (FuDR), are widely used in cancer treatment, but their efficacy is limited by adaptive resistance driven by TYMS upregulation. The upstream mechanisms controlling TYMS expression remain poorly defined. Here, we identify INPPL1 (SHIP2) as a critical regulator of TYMS expression and fluoropyrimidine response in breast cancer cells. We show that SHIP2 enhances basal and drug-induced TYMS expression at the transcriptional level independently of its phosphatase activity. Mechanistically, SHIP2 increases SRC levels and nuclear accumulation of {beta}-catenin, driving TYMS expression. Inhibition of SRC or {beta}-catenin suppresses TYMS induction and restores sensitivity to FuDR. Importantly, SHIP2 rewires TYMS regulation from a P53-dependent program to a {beta}-catenin-driven pathway, enabling sustained TYMS expression under chemotherapeutic stress. Consistent with this model, differential sensitivity to SHIP2 depletion correlates with baseline TYMS levels across cell lines. Analysis of patient cancer datasets reveals that high INPPL1 expression correlates with increased TYMS levels and poor clinical outcomes. These findings identify SHIP2 as a non-canonical regulator of TYMS and a potential therapeutic target to overcome fluoropyrimidine resistance.

cancer biology↗

bioRxiv2026

SHIP2 oligomeric states and activity regulate cellular responses to sodium arsenate-induced stress granule dynamics.

Protein dimerization plays a central role in regulating enzymatic activity, signal transduction, and transcription factor function. Within the PI3K family, different modes of oligomerization have been reported. However, the oligomerization of lipid 5-phosphatases and its functional consequences have not been described. Here, we show for the first time that the lipid 5-phosphatase SHIP2 exists as a homodimer in cells, with its N-terminal region serving as the primary dimerization domain. We further demonstrate that SHIP2 dimerization has no major impact on its catalytic activity but instead profoundly affects its interactome. Interestingly, we identify the stress granule marker G3BP1 as one of the SHIP2 interactors whose association is moderately influenced by SHIP2 oligomerization states. Furthermore, we show that changes in SHIP2 protein levels, enzymatic activity, and oligomeric state alter the cellular response to sodium arsenate-induced stress. In addition, variation in SHIP2 levels and activity affects stress granule size and dynamics. Together, these findings identify SHIP2 oligomerization as a previously unrecognized regulatory mechanism linking phosphoinositide signaling to stress granule biology.

biochemistry↗

bioRxiv2025

Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.

Masitinib is an oral tyrosine kinase inhibitor developed initially for the treatment of mastocytosis. Preclinical studies suggest that masitinib can modulate mast cell activity and neuroinflammation, making it a potential therapeutic candidate for neurodegenerative diseases. However, clinical outcomes remain inconclusive, which may be linked to a lack of understanding of its molecular mechanism of action and potential off-target effects. Using a panel of cancer cell lines, we found that masitinib suppresses mTORC1 activity while simultaneously inducing AKT phosphorylation. Interestingly, thermal proteome profiling analysis revealed that lysosomal proteins were the most thermally affected by masitinib. Using large unilamellar vesicle systems that mimic the lipid composition and physicochemical environment of lysosomal membranes, we observed that masitinib preferentially accumulates in acidic vesicle membranes, consistent with a pH-dependent trapping mechanism. Furthermore, cellular assays demonstrated that masitinib disrupts autophagy by impairing lysosomal acidification. Together, these findings elucidate the lysosomal accumulation of masitinib, providing a molecular basis for its mechanism of action.

pharmacology and toxicology↗

bioRxiv2025

Mechanistic Insights into TYSM Protein Regulation by mTORC2 in Response to Chemotherapy.

Transcriptional and translation control of thymidylate synthase (TYMS) is poorly understood, particularly in response to chemotherapeutic drugs such as 5-Fluorouracil (5-FU) and its derivatives. The current study addressed this gap by demonstrating a biphasic response in TYMS protein levels upon 5-FU treatment. Indeed, we observe an initial reduction within the first few hours, followed by a marked increase at 24 hours. These changes occurred independently of transcriptional regulation, as TYMS mRNA levels remained stable during the early phase and showed only a moderate increase later. We further showed that neither autophagy nor proteasomal degradation contributed to this dynamic, but instead it is driven by change in its translation. Using thermal proteome profiling, we identified SIN1, a key component of the mTORC2 complex, as a key regulator of TYMS protein levels. Functional studies revealed that SIN1 depletion negatively alters TYMS levels and dynamics and sensitizes cancer cells to 5-FU-mediated cell death. These findings uncover a novel mechanism controlling TYMS protein levels and suggest that targeting SIN1 may represent a promising strategy to enhance the therapeutic efficacy of 5-FU-based treatments.

biochemistry↗

bioRxiv2020

The Atlas of Inflammation-Resolution (AIR)

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi and interdisciplinary approach necessary. This Atlas of Inflammation Resolution (AIR) is a web-based resource capturing the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. The AIR serves as an open access knowledgebase, including a gateway to numerous public databases. It is furthermore possible for the user to map experimental data onto the molecular interaction maps of the AIR, providing the basis for bioinformatics analyses and systems biology approaches. By mapping experimental data onto the Atlas, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The Atlas of Inflammation Resolution was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses.

immunology↗