We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet−nuclear extract (comet−NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.
Addressing nanomedicine resistance is critical for its ultimate clinical success; despite this, advancing the therapeutic designs for cancer therapy are rarely discussed in the literature.
Emerging evidences suggest that function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyzed lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in patient-derived melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in two distinct in vivo models (mouse and zebrafish) significantly reduces invasive outgrowth. Our study provides a direct demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting that lysosome positioning could potentially be used for the diagnosis of metastatic melanoma.
Introduction Resistance of cancer cells to bare nanomaterials is rarely discussed but critical for clinical success in nanomedicine. Insight to the nanoresistance mechanism can optimise precision nanomedicine. Here, we report that ferroptosis is the battlefield between zero-valent iron nanoparticles (ZVI NPs) and cancer cells, which dominants therapeutic efficacy and development of resistance. Accumulating mitochondrial lipid peroxidation (LPO) and attenuation of glutathione peroxidase (GPx) are the hallmarkers for ZVI-induced ferroptosis. Although refractory cancer cells can defense above challenges, ferroptosis inducers (FINs) can sensitise them without affecting normal cells. Our findings suggest that ferroptosis pathway may provide druggable targets to reverse resistance for ZVI-based nanomedicine. Material and methods Preparation of ZVI NPs Cell survival assay Subcellular ROS analysis Assessing mitochondrial functions Live-cell imaging Western blot of subcellular fraction Transcriptome analysis Xenograft model Results and discussions Oral cancer cells exhibit distinct sensitivity to ZVI NPs. In the sensitive cells, the core mechanism of ZVI-cytotoxicity is ferroptosis and it is different from FINs-induced ferroptosis. It is caused by mitochondrial LPO and is followed by loss of mitochondrial function. In addition, GPx proteins were declined in subcellular organelles after ZVI NPs treatment. In contrast, ZVI-refractory cells were able to maintain GPx. They harboured higher ROS-scavenging capacity and higher mitochondrial activity to escape from crisis. The transcriptome of paired ZVI-sensitive/refractory clones showed some routes may participate the ZVI-resistance such as NADPH supply, ROS-detoxification, and PUFA metabolism. Finally, we confirmed that integrating FINs with ZVI NPs could revert resistant cancers to be treatable while still sparing normal cells in vitro and in vivo. Conclusion The ferroptosis mechanism governing the selective ZVI-cytotoxicity toward cancer cells and their links to nanoresistance were reported for the first time. Our results suggest that ferroptosis is the nexus for ZVI-based anticancer nanotherapy and its resistance development. Detection and modulation of ferroptosis-susceptibility not only provide a biomarker-based nanomedicine, but also open a novel gateway to improve clinical outcome by management of nanoresistance. We anticipate these findings will inspire new concepts in NPs-induced ferroptosis, NPs-resistance, and anti-resistance strategy for precision nanomedicine.
ABSTRACT Under metabolic stress, cellular components can assemble into distinct membraneless organelles for adaptation. One such example is cytidine 5′-triphosphate synthase (CTPS, for which there are CTPS1 and CTPS2 forms in mammals), which forms filamentous structures under glutamine deprivation. We have previously demonstrated that histidine (His)-mediated methylation regulates the formation of CTPS filaments to suppress enzymatic activity and preserve the CTPS protein under glutamine deprivation, which promotes cancer cell growth after stress alleviation. However, it remains unclear where and how these enigmatic structures are assembled. Using CTPS–APEX2-mediated in vivo proximity labeling, we found that synaptosome-associated protein 29 (SNAP29) regulates the spatiotemporal filament assembly of CTPS along the cytokeratin network in a keratin 8 (KRT8)-dependent manner. Knockdown of SNAP29 interfered with assembly and relaxed the filament-induced suppression of CTPS enzymatic activity. Furthermore, APEX2 proximity labeling of keratin 18 (KRT18) revealed a spatiotemporal association of SNAP29 with cytokeratin in response to stress. Super-resolution imaging suggests that during CTPS filament formation, SNAP29 interacts with CTPS along the cytokeratin network. This study links the cytokeratin network to the regulation of metabolism by compartmentalization of metabolic enzymes during nutrient deprivation.
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