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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 -
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 -
International Journal of Molecular... Feb 2021Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere... (Review)
Review
Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.
Topics: Anoikis; Autophagy; Cell Survival; Cellular Senescence; Drug Resistance, Neoplasm; Exosomes; Extracellular Matrix; Humans; Neoplasm Metastasis; Neoplasms; Plasminogen; Plasminogen Inactivators; Signal Transduction
PubMed: 33669052
DOI: 10.3390/ijms22052304 -
Biomedicine & Pharmacotherapy =... Jul 2024Tumor metastasis occurs in hepatocellular carcinoma (HCC), leading to tumor progression and therapeutic failure. Anoikis is a matrix detachment-induced apoptosis, also... (Review)
Review
Tumor metastasis occurs in hepatocellular carcinoma (HCC), leading to tumor progression and therapeutic failure. Anoikis is a matrix detachment-induced apoptosis, also known as detachment-induced cell death, and mechanistically prevents tumor cells from escaping their native extracellular matrix to metastasize to new organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat HCC. Several natural and synthetic products induce anoikis in HCC cells and in vivo models. Here, we first briefly summarize the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in HCC metastasis. Then we discuss the therapeutic potential of pharmacological induction of anoikis as a potential treatment against HCC. Finally, we discuss the key limitations of this therapeutic paradigm and propose possible strategies to overcome them. Cumulatively this review suggests that the pharmacological induction of anoikis can be used a promising therapeutic modality against HCC.
Topics: Anoikis; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Animals; Antineoplastic Agents; Neoplasm Metastasis
PubMed: 38843588
DOI: 10.1016/j.biopha.2024.116878 -
Biomolecules Jan 2021Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating... (Review)
Review
Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating tumor cells (CTCs) survives dissemination due to anoikis, shear forces and elimination by the immune system. However, all metastases originate from CTCs capable of surviving and extravasating into distant tissue to re-initiate a tumor. Metastasis initiation is not always immediate as disseminated tumor cells (DTCs) may enter a non-dividing state of cell dormancy. Cancer dormancy is a reversible condition that can be maintained for many years without being clinically detectable. Subsequently, late disease relapses are thought to be due to cancer cells ultimately escaping from dormant state. Cancer dormancy is usually associated with minimal residual disease (MRD), where DTCs persist after intended curative therapy. Thus, MRD is commonly regarded as an indicator of poor prognosis in all cancers. In this review, we examine the current understanding of MRD and immunity during cancer progression to metastasis and discuss clinical perspectives for oncology.
Topics: Animals; Apoptosis; Clinical Trials as Topic; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immune System; Immunotherapy; Medical Oncology; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Neoplastic Cells, Circulating; Prognosis; Signal Transduction
PubMed: 33498251
DOI: 10.3390/biom11020130 -
Journal of Functional Biomaterials Jul 2021Literature in the field of stem cell therapy indicates that, when stem cells in a state of single-cell suspension are injected systemically, they show poor in vivo... (Review)
Review
Literature in the field of stem cell therapy indicates that, when stem cells in a state of single-cell suspension are injected systemically, they show poor in vivo survival, while such cells show robust cell survival and regeneration activity when transplanted in the state of being attached on a biomaterial surface. Although an attachment-deprived state induces anoikis, when cell-surface engineering technology was adopted for stem cells in a single-cell suspension state, cell survival and regenerative activity dramatically improved. The biochemical signal coming from ECM (extracellular matrix) molecules activates the cell survival signal transduction pathway and prevents anoikis. According to the target disease, various therapeutic cells can be engineered to improve their survival and regenerative activity, and there are several types of biomaterials available for cell-surface engineering. In this review, biomaterial types and application strategies for cell-surface engineering are presented along with their expected efficacy.
PubMed: 34287337
DOI: 10.3390/jfb12030041 -
Frontiers in Oncology 2023
PubMed: 38023204
DOI: 10.3389/fonc.2023.1268519 -
Frontiers in Cell and Developmental... 2021Glomerular podocytes are characterized by terminally differentiated epithelial cells with limited proliferating ability; thus, podocyte loss could not be fully... (Review)
Review
Glomerular podocytes are characterized by terminally differentiated epithelial cells with limited proliferating ability; thus, podocyte loss could not be fully compensated by podocyte regeneration. A large body of clinical studies collectively demonstrated that podocyte loss correlated with glomerular diseases progression. Both podocyte death and podocyte detachment lead to podocyte loss; however, which one is the main cause remains controversial. Up to date, multiple mechanisms are involved in podocyte death, including programmed apoptotic cell death (apoptosis and anoikis), programmed nonapoptotic cell death (autophagy, entosis, and podoptosis), immune-related cell death (pyroptosis), and other types of cell death (necroptosis and mitotic catastrophe-related cell death). Apoptosis is considered a common mechanism of podocyte loss; however, most of the data were generated and the evidence of podocyte apoptosis is limited. The isolation of podocytes in the urine and subsequent culture of urinary podocytes suggest that detachment of viable podocytes could be another important mechanism for podocyte loss. In this review, we summarize recent advances that address this controversial topic on the specific circumstances of podocyte loss.
PubMed: 34881244
DOI: 10.3389/fcell.2021.771931 -
Cell Death & Disease Jan 2022The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is...
The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.
Topics: Activating Transcription Factor 4; Aged; Animals; Anoikis; Autophagy; Beclin-1; Cell Line, Tumor; Cell Membrane; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Hyaluronoglucosaminidase; Male; Mice; Phosphorylation; Prostatic Neoplasms; Protein Kinase C-alpha; Proto-Oncogene Proteins c-bcl-2
PubMed: 35013120
DOI: 10.1038/s41419-021-04494-x