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Journal of Experimental & Clinical... Jun 2024Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are...
BACKGROUND
Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore.
METHODS
We investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan-Meier plotter database and clinical breast cancer tissue samples.
RESULTS
We demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3β-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo.
CONCLUSIONS
Our findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.
Topics: Humans; Triple Negative Breast Neoplasms; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice; Animals; Organelle Biogenesis; Phosphorylation; Glycogen Synthase Kinase 3 beta; Naphthoquinones; Female; Cancer-Associated Fibroblasts; Cell Line, Tumor; Mice, SCID; Neoplasm Metastasis; Mice, Inbred NOD; Mitochondria; Xenograft Model Antitumor Assays
PubMed: 38937832
DOI: 10.1186/s13046-024-03101-z -
International Journal of Molecular... Jun 2024Arsenic compounds have been used as therapeutic alternatives for several diseases including cancer. In the following work, we obtained arsenic nanoparticles (AsNPs)...
Arsenic compounds have been used as therapeutic alternatives for several diseases including cancer. In the following work, we obtained arsenic nanoparticles (AsNPs) produced by an anaerobic bacterium from the , in northern Chile, and evaluated their effects on the human oral squamous carcinoma cell line OECM-1. Resazurin reduction assays were carried out on these cells using 1-100 µM of AsNPs, finding a concentration-dependent reduction in cell viability that was not observed for the non-tumoral gastric mucosa-derived cell line GES-1. To establish if these effects were associated with apoptosis induction, markers like Bcl2, Bax, and cleaved caspase 3 were analyzed via Western blot, executor caspases 3/7 via luminometry, and DNA fragmentation was analyzed by TUNEL assay, using 100 µM cisplatin as a positive control. OECM-1 cells treated with AsNPs showed an induction of both extrinsic and intrinsic apoptotic pathways, which can be explained by a significant decrease in P-Akt/Akt and P-ERK/ERK relative protein ratios, and an increase in both PTEN and p53 mRNA levels and Bit-1 relative protein levels. These results suggest a prospective mechanism of action for AsNPs that involves a potential interaction with extracellular matrix (ECM) components that reduces cell attachment and subsequently triggers , an anchorage-dependent type of apoptosis.
Topics: Humans; Anoikis; Apoptosis; Cell Line, Tumor; Nanoparticles; Arsenic; Cell Survival; Mouth Neoplasms; Caspase 3; Signal Transduction; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-akt
PubMed: 38928430
DOI: 10.3390/ijms25126723 -
BMC Biology Jun 2024The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly...
BACKGROUND
The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear.
RESULTS
This study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models.
CONCLUSIONS
These findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism.
Topics: Vimentin; Integrin beta1; Anoikis; Humans; Animals; Cell Survival; Mice; Cell Line, Tumor; Phosphorylation; p21-Activated Kinases
PubMed: 38915055
DOI: 10.1186/s12915-024-01942-w -
Cancer Letters Jun 2024Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research,...
Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research, targeting anoikis resistance remians a challenge. Here, we identify argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle, is markedly upregulated in OC cells in detached culture and is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by elevated ASS1 activates AMPK and its downstream factor, CPT1A. Then, ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses ASS1-induced FAO. Our study gives some new functional insights into OC metabolism and represents a shift from traditional views, expanding ASS1's relevance beyond nitrogen metabolism to fatty acid metabolism. It uncovers how ASS1-induced FAO disrupts the AMP/ATP balance, leading to AMPK activation. By identifying the ASS1/AMPK/CPT1A axis as crucial for OC anoikis resistance and metastasis, our study opens up new avenues for therapeutic interventions.
PubMed: 38914306
DOI: 10.1016/j.canlet.2024.217082 -
Advanced Science (Weinheim,... Jun 2024Cell therapy is a potential novel treatment for cardiac regeneration and numerous studies have attempted to transplant cells to regenerate the myocardium lost during...
Cell therapy is a potential novel treatment for cardiac regeneration and numerous studies have attempted to transplant cells to regenerate the myocardium lost during myocardial infarction. To date, only minimal improvements to cardiac function have been reported. This is likely to be the result of low cell retention and survival following transplantation. This study aimed to improve the delivery and engraftment of viable cells by using an injectable microcarrier that provides an implantable, biodegradable substrate for attachment and growth of cardiomyocytes derived from induced pluripotent stem cells (iPSC). We describe the fabrication and characterisation of Thermally Induced Phase Separation (TIPS) microcarriers and their surface modification to enable iPSC-derived cardiomyocyte attachment in xeno-free conditions is described. The selected formulation resulted in iPSC attachment, expansion, and retention of pluripotent phenotype. Differentiation of iPSC into cardiomyocytes on the microcarriers is investigated in comparison with culture on 2D tissue culture plastic surfaces. Microcarrier culture is shown to support culture of a mature cardiomyocyte phenotype, be compatible with injectable delivery, and reduce anoikis. The findings from this study demonstrate that TIPS microcarriers provide a supporting matrix for culturing iPSC and iPSC-derived cardiomyocytes in vitro and are suitable as an injectable cell-substrate for cardiac regeneration.
PubMed: 38900068
DOI: 10.1002/advs.202404355 -
International Journal of Molecular... May 2024Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the...
Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells.
Topics: Humans; Anoikis; Colorectal Neoplasms; Sirtuins; Gene Expression Regulation, Neoplastic; Cell Cycle Proteins; Cell Line, Tumor; Intracellular Signaling Peptides and Proteins; Down-Regulation; Signal Transduction; Epigenesis, Genetic
PubMed: 38891773
DOI: 10.3390/ijms25115585 -
Molecular Diagnosis & Therapy Jul 2024Apoptosis, or programmed cell death, maintains tissue homeostasis by eliminating damaged or unnecessary cells. However, cells can evade this process, contributing to... (Review)
Review
Apoptosis, or programmed cell death, maintains tissue homeostasis by eliminating damaged or unnecessary cells. However, cells can evade this process, contributing to conditions such as cancer. Escape mechanisms include anoikis, mitochondrial DNA depletion, cellular FLICE inhibitory protein (c-FLIP), endosomal sorting complexes required for transport (ESCRT), mitotic slippage, anastasis, and blebbishield formation. Anoikis, triggered by cell detachment from the extracellular matrix, is pivotal in cancer research due to its role in cellular survival and metastasis. Mitochondrial DNA depletion, associated with cellular dysfunction and diseases such as breast and prostate cancer, links to apoptosis resistance. The c-FLIP protein family, notably CFLAR, regulates cell death processes as a truncated caspase-8 form. The ESCRT complex aids apoptosis evasion by repairing intracellular damage through increased Ca2+ levels. Antimitotic agents induce mitotic arrest in cancer treatment but can lead to mitotic slippage and tetraploid cell formation. Anastasis allows cells to resist apoptosis induced by various triggers. Blebbishield formation suppresses apoptosis indirectly in cancer stem cells by transforming apoptotic cells into blebbishields. In conclusion, the future of apoptosis research offers exciting possibilities for innovative therapeutic approaches, enhanced diagnostic tools, and a deeper understanding of the complex biological processes that govern cell fate. Collaborative efforts across disciplines, including molecular biology, genetics, immunology, and bioinformatics, will be essential to realize these prospects and improve patient outcomes in diverse disease contexts.
Topics: Humans; Apoptosis; Neoplasms; Endosomal Sorting Complexes Required for Transport; Animals; CASP8 and FADD-Like Apoptosis Regulating Protein
PubMed: 38890247
DOI: 10.1007/s40291-024-00718-w -
Journal of Immunotherapy (Hagerstown,... Jun 2024From databases of the Cancer Genome Atlas (TCGA) and GSE42568, transcriptome data of breast cancer patients was obtained. Then, anoikis-related genes (ANRGs) were...
From databases of the Cancer Genome Atlas (TCGA) and GSE42568, transcriptome data of breast cancer patients was obtained. Then, anoikis-related genes (ANRGs) were identified and constructed a risk score system. As a threshold value, the median risk score was used to stratify patients into low-risk and high-risk groups. Kaplan-Meier analysis was then conducted to evaluate the prognostic ability of the risk score system, which was validated using GSE7390. Furthermore, we identified potential enrichment of function and tumor immune infiltration in the model. Finally, the biological functions of a risk gene (EPB41L4B) in breast cancer were investigated through in vitro experiments. We constructed a risk score system via 9 prognosis ANRGs (CXCL2, EPB41L4B, SLC7A5, SFRP1, SDC1, BHLHE41, SPINT1, KRT15, and CD24). The Kaplan-Meier analysis showed that both TCGA-BRCA (training set) and GSE7390 (testing set) patients with high-risk status had significantly worse survival outcomes. In addition, the calibration plots were in good agreement with the prognosis prediction. Breast cancer patients with immunosuppressive microenvironment could be screened using risk groups since risk scores were correlated negatively with ESTIMATE score, tumor-infiltration lymphocytes, immune checkpoints, and chemotactic factors. Furthermore, cellular viability and cell migration of cancerous breast cells were inhibited and apoptosis was promoted by down-regulation of EPB41L4B gene expression. Based on ANRGs, a 9-gene prognostic model could be developed to predict breast cancer prognosis; moreover, patients of the high-risk group were in an immunosuppressed tumor microenvironment.
PubMed: 38864225
DOI: 10.1097/CJI.0000000000000523 -
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 -
Aging Jun 2024Lung adenocarcinoma (LUAD) is the most common type of lung cancer and is characterized by a high death rate and a poor prospect for survival. Anoikis, which is a kind of...
Lung adenocarcinoma (LUAD) is the most common type of lung cancer and is characterized by a high death rate and a poor prospect for survival. Anoikis, which is a kind of programmed cell apoptosis, is an important factor in the advancement of tumors. Nonetheless, the function of anoikis-related lncRNAs (ARLRs) in LUAD is still not well understood. The TCGA database was queried for genomic and clinical information. A prognostic signature for ARLRs was established via the use of coexpression analysis and Cox regression. Validation of the model's accuracy was conducted utilizing K-M curves and receiver operating characteristic (ROC) curves, and the signature was utilized to develop a nomogram. LncRNAs were implicated in the progression of tumors, as determined by functional enrichment analysis. There was an improvement in prognosis, increased immune cell infiltration, and higher immune scores among the low-risk patients. Additionally, we found that the two groups had varied anticancer drug sensitivities, which could help guide treatment. The impact of one ARLR, AC026355.2, on migration and invasion was validated by experiments in LUAD cells. Herein, a new lncRNA signature associated with anoikis was identified and estimated, potentially serving as a prognostic indicator for LUAD patients.
Topics: Humans; RNA, Long Noncoding; Anoikis; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Female; Male; Cell Line, Tumor; Nomograms; Middle Aged; Cell Movement
PubMed: 38850527
DOI: 10.18632/aging.205905