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Theranostics 2020Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. The 2-DIGE, MALDI-TOF/TOF MS and...
Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin () transcription . Nude mice and conditional transgenic mice were used to investigate the findings . We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote transcription, which conferred resistance to anoikis in GC cells and . Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.
Topics: Animals; Anoikis; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Chemotherapy, Adjuvant; Female; Gastrectomy; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Male; Mice; Mice, Transgenic; Myosin Heavy Chains; Phosphorylation; Promoter Regions, Genetic; Staurosporine; Stomach; Stomach Neoplasms; Transcriptional Activation; Up-Regulation; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; beta Catenin
PubMed: 32685004
DOI: 10.7150/thno.46001 -
Pharmacology & Therapeutics Oct 2023Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its... (Review)
Review
Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.
Topics: Humans; Neoplasms; Signal Transduction; Anoikis; Neoplasm Metastasis; Epithelial-Mesenchymal Transition; Tumor Microenvironment
PubMed: 37661054
DOI: 10.1016/j.pharmthera.2023.108522 -
Proceedings of the National Academy of... Jun 2023Although recent studies demonstrate active mitochondrial metabolism in cancers, the precise mechanisms through which mitochondrial factors contribute to cancer...
Although recent studies demonstrate active mitochondrial metabolism in cancers, the precise mechanisms through which mitochondrial factors contribute to cancer metastasis remain elusive. Through a customized mitochondrion RNAi screen, we identified succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) as a critical anoikis resistance and metastasis driver in human cancers. Mechanistically, SUCLA2, but not the alpha subunit of its enzyme complex, relocates from mitochondria to the cytosol upon cell detachment where SUCLA2 then binds to and promotes the formation of stress granules. SUCLA2-mediated stress granules facilitate the protein translation of antioxidant enzymes including catalase, which mitigates oxidative stress and renders cancer cells resistant to anoikis. We provide clinical evidence that SUCLA2 expression correlates with catalase levels as well as metastatic potential in lung and breast cancer patients. These findings not only implicate SUCLA2 as an anticancer target, but also provide insight into a unique, noncanonical function of SUCLA2 that cancer cells co-opt to metastasize.
Topics: Humans; Catalase; Stress Granules; Succinate-CoA Ligases; Oxidation-Reduction; Neoplasms
PubMed: 37253003
DOI: 10.1073/pnas.2217332120 -
Cell Communication and Signaling : CCS Sep 2023Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous... (Review)
Review
Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. Video Abstract.
Topics: Anoikis; Proteolysis; Caspases; Mitochondria; Protein Processing, Post-Translational
PubMed: 37667281
DOI: 10.1186/s12964-023-01247-5 -
Thoracic Cancer Jan 2023Lung adenocarcinoma (LUAD) is the most prevalent histotype of non-small cell lung cancer. Anoikis, an alternative form of programmed cell death, plays a pivotal role in...
BACKGROUND
Lung adenocarcinoma (LUAD) is the most prevalent histotype of non-small cell lung cancer. Anoikis, an alternative form of programmed cell death, plays a pivotal role in cancer invasion and metastasis, preventing the detached cancer cells from readhering to other substrates for abnormal proliferation. The aim of this study was to conduct a comprehensive analyses of the prognostic implications of anoikis-related genes (ARGs) in LUAD.
METHODS
ARGs were selected from The Cancer Genome Atlas (TCGA) database and Genecards dataset using differential expression analysis. The signature incorporating ARGs was identified using univariate Cox regression analysis and LASSO regression analysis. Furthermore, a nomogram containing the signature and clinical information was developed through univariate and multivariate Cox regression analysis. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves were applied to evaluate the predictive validity of these risk models. Finally, functional analysis of the selected ARGs in signature and analysis of immune landscape were also conducted.
RESULTS
A 16-gene signature was integrated to stratify LUAD patients into different survival risk groups. The prognostic risk score generated from the signature and TNM stage were identified as independent prognostic factors and utilized to develop a nomogram. Both the signature and the nomogram showed satisfactory prediction performance in predicting overall survival (OS) of LUAD patients. The ARGs were enriched in several biological functions and signaling pathways. Finally, differences of immune landscape were investigated among the high- and low-risk groups stratified by the signature.
CONCLUSIONS
This study revealed potential relationships between ARGs and prognosis of LUAD. The prognostic predictors identified in present study could be utilized as potential biomarkers for clinical applications.
Topics: Humans; Anoikis; Carcinoma, Non-Small-Cell Lung; Tumor Microenvironment; Lung Neoplasms; Prognosis; Adenocarcinoma of Lung
PubMed: 36507553
DOI: 10.1111/1759-7714.14766 -
Science Signaling Mar 2023Membrane blebs form signaling hubs that enable tumor cells to resist death by anoikis.
Membrane blebs form signaling hubs that enable tumor cells to resist death by anoikis.
Topics: Anoikis; Signal Transduction
PubMed: 36976865
DOI: 10.1126/scisignal.adh9176 -
Cell Death & Disease Sep 2021Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density...
Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Animals; Anoikis; Apoptosis; Base Sequence; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholesterol; Disease Progression; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Prognosis; Signal Transduction; Transcription Factors; Transcription, Genetic; Up-Regulation; Mice
PubMed: 34518524
DOI: 10.1038/s41419-021-04132-6 -
Drug Resistance Updates : Reviews and... Jul 2024Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to... (Review)
Review
Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.
Topics: Anoikis; Humans; Neoplasms; Antineoplastic Agents; Animals; Drug Resistance, Neoplasm; Neoplasm Metastasis
PubMed: 38850692
DOI: 10.1016/j.drup.2024.101099 -
Cancers Sep 2022Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it... (Review)
Review
Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.
PubMed: 36230714
DOI: 10.3390/cancers14194791 -
Journal of Translational Medicine Jul 2023Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis...
BACKGROUND
Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear.
METHODS
Immunohistochemistry (IHC) was used to examine Nrf2 expression in CC. Wound healing assay and transwell analysis were used to evaluate the migration ability of CC cells. Western blot, qTR-PCR and immunofluorescent staining were used to verify the expression level of Nrf2, the EMT associated markers and anoikis associated proteins. Flow cytometry assays and cell counting were used to detect the apoptosis of cervical cancer cells. The lung and lymph node metastatic mouse model were established for studies in vivo. The interaction between Nrf2 and Snail1 was confirmed by rescue-of-function assay.
RESULTS
When compared with cervical cancer patients without lymph node metastasis, Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. In vivo, a xenograft assay also showed that Nrf2 facilitated both pulmonary and lymphatic distant metastasis of cervical cancer. Rescue-of-function assay further revealed the mechanism that Nrf2 impacted the metastasis of CC through Snail1.
CONCLUSION
Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.
Topics: Female; Animals; Mice; Humans; Cell Line, Tumor; Lymphatic Metastasis; NF-E2-Related Factor 2; Uterine Cervical Neoplasms; HeLa Cells; Epithelial-Mesenchymal Transition; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Neoplasm Metastasis
PubMed: 37403143
DOI: 10.1186/s12967-023-04287-0