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1.
Exp Mol Med ; 56(4): 877-889, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38580812

RESUMO

Extracellular vesicles (EVs), including exosomes, are increasingly recognized as potent mediators of intercellular communication due to their capacity to transport a diverse array of bioactive molecules. They assume vital roles in a wide range of physiological and pathological processes and hold significant promise as emerging disease biomarkers, therapeutic agents, and carriers for drug delivery. Exosomes encompass specific groups of membrane proteins, lipids, nucleic acids, cytosolic proteins, and other signaling molecules within their interior. These cargo molecules dictate targeting specificity and functional roles upon reaching recipient cells. Despite our growing understanding of the significance of exosomes in diverse biological processes, the molecular mechanisms governing the selective sorting and packaging of cargo within exosomes have not been fully elucidated. In this review, we summarize current insights into the molecular mechanisms that regulate the sorting of various molecules into exosomes, the resulting biological functions, and potential clinical applications, with a particular emphasis on their relevance in cancer and other diseases. A comprehensive understanding of the loading processes and mechanisms involved in exosome cargo sorting is essential for uncovering the physiological and pathological roles of exosomes, identifying therapeutic targets, and advancing the clinical development of exosome-based therapeutics.


Assuntos
Exossomos , Neoplasias , Exossomos/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Neoplasias/terapia , Animais , Comunicação Celular , Transporte Biológico
2.
STAR Protoc ; 4(3): 102444, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37436904

RESUMO

Exosomes mediate intracellular communication between cancer cells and the local/distant microenvironment, which promotes systemic dissemination of cancer. Here, we present a protocol for tumor-derived exosome isolation and in vivo metastasis evaluation in a mouse model. We describe steps for isolating and characterizing exosomes, establishing a metastatic mouse model, and injecting exosomes into mouse. We then detail hematoxylin and eosin staining and analysis. This protocol can be used to investigate exosome function and identify unexplored metastatic regulators related to exosome biogenesis. For complete details on the use and execution of this protocol, please refer to Lee et al. (2023).1.


Assuntos
Exossomos , Neoplasias , Animais , Camundongos , Neoplasias/patologia , Microambiente Tumoral
3.
Dev Cell ; 58(4): 320-334.e8, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36800996

RESUMO

Exosomes transport a variety of macromolecules and modulate intercellular communication in physiology and disease. However, the regulation mechanisms that determine exosome contents during exosome biogenesis remain poorly understood. Here, we find that GPR143, an atypical GPCR, controls the endosomal sorting complex required for the transport (ESCRT)-dependent exosome biogenesis pathway. GPR143 interacts with HRS (an ESCRT-0 Subunit) and promotes its association to cargo proteins, such as EGFR, which subsequently enables selective protein sorting into intraluminal vesicles (ILVs) in multivesicular bodies (MVBs). GPR143 is elevated in multiple cancers, and quantitative proteomic and RNA profiling of exosomes in human cancer cell lines showed that the GPR143-ESCRT pathway promotes secretion of exosomes that carry unique cargo, including integrins signaling proteins. Through gain- and loss-of-function studies in mice, we show that GPR143 promotes metastasis by secreting exosomes and increasing cancer cell motility/invasion through the integrin/FAK/Src pathway. These findings provide a mechanism for regulating the exosomal proteome and demonstrate its ability to promote cancer cell motility.


Assuntos
Exossomos , Neoplasias , Humanos , Animais , Camundongos , Exossomos/metabolismo , Proteômica , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Transporte Proteico , Transporte Biológico , Corpos Multivesiculares/metabolismo , Neoplasias/metabolismo , Proteínas do Olho/metabolismo , Glicoproteínas de Membrana/metabolismo
4.
J Control Release ; 349: 367-378, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35809662

RESUMO

The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer drug candidate because it selectively binds to the proapoptotic death receptors, which are frequently overexpressed in a wide range of cancer cells, subsequently inducing strong apoptosis in these cells. However, the therapeutic benefit of TRAIL has not been clearly proven, mainly because of its poor pharmacokinetic characteristics and frequent resistance to its application caused by the activation of a survival signal via the EGF/epidermal growth factor receptor (EGFR) signaling pathway. Here, a lumazine synthase protein cage nanoparticle isolated from Aquifex aeolicus (AaLS) was used as a multiple ligand-displaying nanoplatform to display polyvalently both TRAIL and EGFR binding affibody molecules (EGFRAfb) via a SpyTag/SpyCatcher protein-ligation system, to form AaLS/TRAIL/EGFRAfb. The dual-ligand-displaying AaLS/TRAIL/EGFRAfb exhibited a dramatically enhanced cytotoxicity on TRAIL-resistant and EGFR-overexpressing A431 cancer cells in vitro, effectively disrupting the EGF-mediated EGFR survival signaling pathway by blocking EGF/EGFR binding as well as strongly activating both the extrinsic and intrinsic apoptotic pathways synergistically. The AaLS/TRAIL/EGFRAfb selectively targeted A431 cancer cells in vitro and actively reached the tumor sites in vivo. The A431 tumor-bearing mice treated with AaLS/TRAIL/EGFRAfb exhibited a significant suppression of the tumor growth without any significant side effects. Collectively, these findings showed that the AaLS/TRAIL/EGFRAfb could be used as an effective protein-based therapeutic for treating EGFR-positive cancers, which are difficult to manage using mono-therapeutic approaches.


Assuntos
Antineoplásicos , Nanopartículas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico , Receptores ErbB/metabolismo , Ligantes , Camundongos , Receptores de Morte Celular , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
5.
Biochem Biophys Res Commun ; 577: 103-109, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34509721

RESUMO

As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extracellular ligands and mediate intracellular signal transduction. PLCγ1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLCγ1 and cancer behavior remains undefined. To investigate the role of PLCγ1 in colorectal carcinogenesis, we generated an intestinal tissue-specific Plcg1 knock out (KO) in adenomatous polyposis coli (Apc) Min/+ mice. Plcg1 deficiency in ApcMin/+ mice showed earlier death, with a higher colorectal tumor incidence in both number and size than in wild-type mice. Mechanistically, inhibition of PLCγ1 increased the levels of its substrate phosphoinositol 4,5-bisphosphate (PIP2) at the plasma membrane and promoted the activation of Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3ß (GSK3ß) to enhance ß-catenin signaling. Enhanced cell proliferation and Wnt/ß-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLCγ1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLCγ1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/ß-catenin-dependent intestinal tumor formation.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Fosfolipase C gama/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Progressão da Doença , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Intestinos/enzimologia , Intestinos/patologia , Estimativa de Kaplan-Meier , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfolipase C gama/deficiência , beta Catenina/metabolismo
6.
Adv Exp Med Biol ; 1187: 23-52, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983572

RESUMO

Breast cancer progression results from subversion of multiple intra- or intercellular signaling pathways in normal mammary tissues and their microenvironment, which have an impact on cell differentiation, proliferation, migration, and angiogenesis. Phospholipases (PLC, PLD and PLA) are essential mediators of intra- and intercellular signaling. They hydrolyze phospholipids, which are major components of cell membrane that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid. Enzymatic processing of phospholipids by phospholipases converts these molecules into lipid mediators that regulate multiple cellular processes, which in turn can promote breast cancer progression. Thus, dysregulation of phospholipases contributes to a number of human diseases, including cancer. This review describes how phospholipases regulate multiple cancer-associated cellular processes, and the interplay among different phospholipases in breast cancer. A thorough understanding of the breast cancer-associated signaling networks of phospholipases is necessary to determine whether these enzymes are potential targets for innovative therapeutic strategies.


Assuntos
Neoplasias da Mama , Fosfolipase D , Humanos , Fosfolipase D/metabolismo , Fosfolipases , Fosfolipídeos , Transdução de Sinais , Microambiente Tumoral , Fosfolipases Tipo C/metabolismo
7.
Oncogenesis ; 10(2): 18, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637676

RESUMO

Mitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

8.
FASEB J ; 34(1): 1270-1287, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914593

RESUMO

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.


Assuntos
Adipócitos/metabolismo , Diferenciação Celular , Glucosilceramidas/metabolismo , Glucosiltransferases/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese , PPAR gama/metabolismo , Animais , Glucosilceramidas/genética , Glucosiltransferases/genética , Humanos , Camundongos , PPAR gama/genética
9.
Cancer Lett ; 471: 72-87, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31838085

RESUMO

Androgen receptor (AR) signaling plays a central role in metabolic reprogramming for prostate cancer (PCa) growth and progression. Mitochondria are metabolic powerhouses of the cell and support several hallmarks of cancer. However, the molecular links between AR signaling and the mitochondria that support the metabolic demands of PCa cells are poorly understood. Here, we demonstrate increased levels of dynamin-related protein 1 (DRP1), a mitochondrial fission mediator, in androgen-sensitive and castration-resistant AR-driven PCa. AR signaling upregulates DRP1 to form the VDAC-MPC2 complex, increases pyruvate transport into mitochondria, and supports mitochondrial metabolism, including oxidative phosphorylation and lipogenesis. DRP1 inhibition activates the cellular metabolic stress response, which involves AMPK phosphorylation, induction of autophagy, and the ER unfolded protein response, and attenuates androgen-induced proliferation. Additionally, DRP1 expression facilitates PCa cell survival under diverse metabolic stress conditions, including hypoxia and oxidative stress. Moreover, we found that increased DRP1 expression was indicative of poor prognosis in patients with castration-resistant PCa. Collectively, our findings link androgen signaling-mediated mitochondrial dynamics to metabolic reprogramming; moreover, they have important implications for understanding PCa progression.


Assuntos
Androgênios/metabolismo , Dinaminas/biossíntese , Mitocôndrias/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Ciclo do Ácido Cítrico , Di-Hidrotestosterona/farmacologia , Dinaminas/antagonistas & inibidores , Dinaminas/genética , Dinaminas/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Masculino , Dinâmica Mitocondrial , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosforilação Oxidativa , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/patologia , Piruvatos/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Regulação para Cima , Canais de Ânion Dependentes de Voltagem/metabolismo
10.
Adv Biol Regul ; 67: 179-189, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174396

RESUMO

Phospholipase C (PLC) is an essential mediator of cellular signaling. PLC regulates multiple cellular processes by generating bioactive molecules such as inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These products propagate and regulate cellular signaling via calcium (Ca2+) mobilization and activation of protein kinase C (PKC), other kinases, and ion channels. PLCγ1, one of the primary subtypes of PLC, is directly activated by membrane receptors, including receptor tyrosine kinases (RTKs), and adhesion receptors such as integrin. PLCγ1 mediates signaling through direct interactions with other signaling molecules via SH domains, as well as its lipase activity. PLCγ1 is frequently enriched and mutated in various cancers, and is involved in the processes of tumorigenesis, including proliferation, migration, and invasion. Although many studies have suggested that PLCγ functions in cell mobility rather than proliferation in cancer, questions remain as to whether PLCγ regulates mitogenesis and whether PLCγ promotes or inhibits proliferation. Moreover, how PLCγ regulates cancer-associated cellular processes and the interplay among other proteins involved in cancer progression have yet to be fully elucidated. In this review, we discuss the current understanding of the role of PLCγ1 in cancer mobility and proliferation.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Fosfolipase C gama/metabolismo , Transdução de Sinais , Animais , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Fosfolipase C gama/genética , Fosfolipases Tipo C/genética , Fosfolipases Tipo C/metabolismo
11.
Oncotarget ; 7(43): 70898-70911, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27765922

RESUMO

G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.


Assuntos
Anfirregulina/metabolismo , Neoplasias da Mama/patologia , Neovascularização Patológica/patologia , Receptores Acoplados a Proteínas G/metabolismo , Microambiente Tumoral , Animais , Apoptose , Mama/irrigação sanguínea , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Separação Celular/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Ácido Láctico/metabolismo , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Curr Pharm Des ; 22(16): 2389-402, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26916018

RESUMO

Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.


Assuntos
Neoplasias/metabolismo , Receptores Adrenérgicos/metabolismo , Estresse Psicológico/metabolismo , Animais , Catecolaminas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
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