مجال التميز | تميز دراسي و بحثي |
البحوث المنشورة |
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البحث (1): | |
عنوان البحث: |
The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death |
رابط إلى البحث: | |
تاريخ النشر: |
13/11/2018 |
موجز عن البحث: |
BACKGROUND: Cytosolic deacetylase histone deacetylase 6 (HDAC6) is involved in the autophagy degradation pathway of malformed proteins, an important survival mechanism in cancer cells. We evaluated modulation of autophagy-related proteins and cell death by the HDAC6-selective inhibitor C1A. METHODS: Autophagy substrates (light chain-3 (LC-3) and p62 proteins) and endoplasmic reticulum (ER) stress phenotype were determined. Caspase-3/7 activation and cellular proliferation assays were used to assess consequences of autophagy modulation. RESULTS: C1A potently resolved autophagy substrates induced by 3-methyladenine and chloroquine. The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatment was consistent with abrogation of autophagosome–lysosome fusion, and decrease of Myc protein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced cell death in malignant cells, demonstrating the complementary roles of the proteasome and autophagy pathways for clearing malformed proteins. Myc-positive neuroblastoma, KRAS-positive colorectal cancer and multiple myeloma cells showed marked cell growth inhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenografts was arrested in vivo by single agent C1A, while combination with bortezomib slowed the growth of colorectal cancer xenografts. CONCLUSIONS: C1A resolves autophagy substrates in malignant cells and induces cell death, warranting its use for in vivo preclinical autophagy research. |
البحث (2): | |
عنوان البحث: |
The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation |
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تاريخ النشر: |
09/01/2019 |
موجز عن البحث: |
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis. |
البحث (3): | |
عنوان البحث: |
Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs |
رابط إلى البحث: | |
تاريخ النشر: |
27/04/2021 |
موجز عن البحث: |
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization. |
هبه أمين بن حسين الساده
دكتوراه
الطب والخدمات الصحية
Imperial College London