Mefloquine disrupts cancer stem cells by inhibiting lysosomal RAB5/7 mediated mitophagy
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PROVIDER: PRJNA476805 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND & AIMS Cancer stem cells (CSCs) establish hierarchy in tumor tissue and a critical role for acquisition of resistance to therapy. Thus, the targeting of CSCs is important. We focused on lysosome which characteristically upregulated in colon CSCs for the aim of CSC targeting and search for new maintenance of CSCs by analyzing the function of CSC targeting drug. METHODS Correlation of lysosomal activity and CSC markers was assessed and single sphere formation and limiting dilution assay were performed, to evaluate CSCs property. Additionally, in vitro and vivo, we evaluated that anticancer drugs, antimalarial drugs, antitumor effect by combining them, and changes in cancer stem cell hierarchy. We performed microarray analyses to compare gene expression patterns from the tumors of treated patient derived xenograft mice. RESULTS LC3B+ or Lysotracker+ cells were characteristically existed in CD44V9+/ CD133+ CSC fraction as a small cell subpopulation. Single sphere formation assay and limiting dilution assay showed higher sphere formation activity and higher tumorigenic activity of LC3B+ or Lysotracker+ cells compared to LC3B－or Lysotracker－cells. Mefloquine treatment significantly decreased CD44v9+/ CD133+ cell number than representative antimalarial drugs, chloroquine and hydroxychloroquine. Mefloquine demonstrated the synergic effect on oxaliplatin and irinotecan. In Microarray analysis, we elucidated that mefloquine disrupted lysosome pathway by inhibiting Rab5 and Rab7. In patient-derived colon cancer tissue xenografted (PDX) mouse model, combined treatment of mefloquine with oxaliplatin or irinotecan drastically abrogated the tumorigenic activity of cancer cells. CONCLUSIONS Lysosomal activity in CSCs is a promising therapeutic target, and repositioning of mefloquine to colon cancer together with conventional chemotherapeutic agent will be a promising strategy for cure of colon cancer.
2018-06-20 | GSE116023 | GEO
Project description:Bladder cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to mitophagy flux impairment at late stage. Mitochondrial reactive oxygen species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and autophagy inhibitor Chloroquine (CQ) to aggravate mitophagy flux impairment promotes NTZ-induced apoptosis, while alleviation of mitophagy flux impairment with ROS scavenger reduced cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors.
2021-03-31 | GSE171129 | GEO
Project description:Nitazoxanide impairs mitophagy flux through ROS-mediated mitophagy initiation and lysosomal dysfunction in bladder cancer
| PRJNA718525 | ENA
Project description:Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. Recent evidence demonstrated the regulation of the autophagy-lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells is not fully elucidated. In this study, we show evidence that suppression of acid alpha-glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of mitophagy via migration of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose- and time-dependent manner. Small interfering RNA against the GAA gene (siGAA) suppressed cell proliferation and promoted apoptosis in gemcitabine-treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vector carrying short hairpin RNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC.
2021-06-28 | GSE153460 | GEO
Project description:ATR licenses PINK1-mediated mitophagy
| PRJNA1023223 | ENA
Project description:The random-pattern skin flap is a crucial technique in reconstructive surgery and flap necrosis caused by ischemia/reperfusion injury is a major postoperative complication. Herein, we investigated the mechanism of mitophagy induced by Melatonin (ML) and its effect on the survival of skin flaps. Our results demonstrated that ML could activate mitophagy, ameliorate oxidative stress and alleviate apoptosis in TBHP-stimulated human umbilical vein endothelial cells in vitro. Inhibiting ML-induced mitophagy considerably abolished its protective effects. Moreover, knockdown of Parkin by siRNA inhibited ML-induced mitophagy, and subsequently exacerbated oxidative stress and apoptosis. Further study demonstrated that inhibition of AMPK reversed these protective effects of ML and downregulated the expression of TFEB. In the vivo study, ML effectively promoted flap survival by activating mitophagy and subsequently ameliorating oxidative stress and mitigating apoptosis. These results established that ML is a potent agent capable for increasing random-pattern skin flap survival by activating Parkin-dependent mitophagy through the AMPK-TFEB signaling pathway.
2022-06-29 | GSE203609 | GEO
Project description:Mitochondrial dysfunction and mitophagy deregulation are hallmark features of aging and age-related pathologies. Urolithin A (UA), a potent mitophagy inducer, is known to confer neuroprotection, maintain muscle integrity, and extend healthspan and lifespan across diverse species. Nonetheless, the molecular mechanisms underlying UA-mediated mitophagy remain largely unknown. Here, we demonstrate that UA treatment modulates cytosolic calcium levels, which are essential for initiating robust mitophagy in both neurons and muscles. Transcriptomic and proteomic analyses reveal that UA facilitates the reorganization of inter-organellar communication between endoplasmic reticulum (ER), lysosomes and mitochondria; processes that are highly dependent on calcium signaling. Our findings suggest that UA induces calcium release from the ER and enhances lysosomal activity, while downstream uptake of released calcium from mitochondria, ultimately leads to mitochondrial fission and the successful execution of mitophagy. Consistently, calcium chelation abolishes UA-induced mitophagy, leading to impaired muscle function and diminishes lifespan extension, underscoring the critical role of calcium dynamics. We further found that UA-induced calcium elevation triggers mitochondrial biogenesis through the activation of UNC-43/CaMKII and SKN-1/Nrf2; these pathways are also critical for healthspan and lifespan extension. In human cells, UA supplementation not only induces mitophagy but also enhances mitochondrial metabolism and prevents stress-induced senescence in a calcium-dependent manner. Ultimately, our findings uncover the mechanistic insights of UA-mediated geroprotection and underscore the central role of calcium dynamics in orchestrating the crosstalk and functional wiring of different cellular compartments, thereby sustaining energy homeostasis and overall organismal physiology.
2026-01-12 | GSE279559 | GEO
Project description:Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria, and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discover that nitric oxide (NO) signaling promotes TRIM21 mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LIR motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21, Nos2, or reconstituted with the East-Asian specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.
2023-06-29 | GSE235994 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases, yet its underlying mechanisms remain poorly understood. Recent evidence suggests that mitochondrial dysfunction and impaired mitophagy play pivotal roles in HFpEF pathogenesis. Thrombospondin 1 (Thbs1), a matricellular protein, is implicated in cardiovascular remodeling, but its role in HFpEF has not been elucidated. Here, we demonstrate that Thbs1 expression is significantly elevated in the myocardium of HFpEF mice and that Thbs1 exacerbates cardiac dysfunction by suppressing mitophagy. Using a well-established "two-hit" mouse model (high-fat diet and L-NAME), we show that AAV9-mediated knockdown of Thbs1 alleviates diastolic dysfunction, cardiac fibrosis, and myocardial inflammation. RNA sequencing and proteomics analyses revealed enrichment of the PI3K/Akt/mTOR pathway in HFpEF hearts, which was attenuated by Thbs1 silencing. Mechanistically, Thbs1 knockdown restored autophagic flux, promoted mitochondrial clearance, and improved mitochondrial homeostasis in cardiomyocytes. These findings establish Thbs1 as a key regulator of impaired mitophagy in HFpEF and suggest that targeting Thbs1 may provide a therapeutic avenue for treating this complex syndrome.
2025-12-30 | GSE305470 | GEO
Project description:The D620N VPS35 mutation disrupts retrograde endosome to Golgi retromer Trafficking. Thus causes lysosome dysfunction, enhances LRRK2 kinase activity and leads to Parkinson’s disease. We employed a LysoTag immunoprecipitation approach to assess how this impacts lysosomes using quantitative proteomics. The VPS35[D620N] mutation alters the expression of over 350 lysosomal proteins, and induces recruitment of LRRK2 phosphorylated Rab proteins to the lysosome, as well as the phosphoRab effector protein RILPL1.
2023-11-28 | PXD042502 | Pride