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1.
Prostate ; 84(7): 644-655, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38409853

RESUMO

BACKGROUND: Lipid reprogramming is a known mechanism to increase the energetic demands of proliferating cancer cells to drive and support tumorigenesis and progression. Elevated lipid droplets (LDs) are a well-known alteration of lipid reprogramming in many cancers, including prostate cancer (PCa), and are associated with high tumor aggressiveness as well as therapy resistance. The mechanism of LD accumulation and specific LD functions are still not well understood; however, it has been shown that LDs can form as a protective mechanism against lipotoxicity and lipid peroxidation in the cell. METHODS: This study investigated the significance of LDs in PCa. This was done by staining, imaging, image quantification, and flow cytometry analysis of LDs in PCa cells. Additionally, lipidomics and metabolomics experiments were performed to assess the difference of metabolites and lipids in control and treatment surviving cancer cells. Lastly, to assess clinical significance, multiple publicly available datasets were mined for LD-related data. RESULTS: Our study demonstrated that prostate and breast cancer cells that survive 72 h of chemotherapy treatment have elevated LDs. These LDs formed in tandem with elevated reactive oxygen species levels to sequester damaged and excess lipids created by oxidative stress, which promoted cell survival. Additionally, by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) (which catalyzes triglyceride synthesis into LDs) and treating with chemotherapy simultaneously, we were able to decrease the overall amount of LDs and increase cancer cell death compared to treating with chemotherapy alone. CONCLUSIONS: Overall, our study proposes a potential combination therapy of DGAT1 inhibitors and chemotherapy to increase cancer cell death.


Assuntos
Gotículas Lipídicas , Neoplasias da Próstata , Masculino , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Próstata/patologia , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia
3.
J Appl Toxicol ; 39(10): 1413-1423, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319435

RESUMO

Lunar regolith samples collected during previous Apollo missions were found to contain components that were established to be toxic to humans; however, the health effects due to inhalation of lunar soil as a whole are still unknown. Macrophages residing in the alveolar sacs of the lungs constitute one of the last lines of defense against inhaled particulates before entry into the bloodstream. Here, we examine the macrophage response to lunar simulants that are similar in chemical composition to the lunar regolith. We assess cytotoxicity, cellular morphology, phagocytosis of simulants and expression of inflammatory markers. Overall, the exposure of macrophages to lunar simulants results in moderate cytotoxicity and marked alteration of cell morphology and uptake of the simulants. Interestingly, simulant exposure decreased proinflammatory gene expression, but may induce an anti-inflammatory phenotype in the cells. These results illustrate that although macrophages phagocytose lunar simulants as a protective response, the simulants do induce a degree of macrophage cell death. Our study reveals some toxicity associated with lunar simulants and supports further evaluation of the inhalation of lunar regolith to understand the risks of exposure fully.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Poeira Cósmica/efeitos adversos , Macrófagos/efeitos dos fármacos , Lua , Solo/química , Voo Espacial , Administração por Inalação , Humanos
4.
Cancer Res ; 78(3): 685-694, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29097606

RESUMO

Glioma-associated microglia and macrophages (GAM), which infiltrate high-grade gilomas, constitute a major cellular component of these lesions. GAM behavior is influenced by tumor-derived cytokines that suppress initial antitumorigenic properties, causing them to support tumor growth and to convert and suppress adaptive immune responses to the tumor. Mice that lack the transmembrane receptor neuropilin-1 (Nrp1), which modulates GAM immune polarization, exhibit a decrease in glioma volumes and neoangiogenesis and an increase in antitumorigenic GAM infiltrate. Here we show that replacing the peripheral macrophage populations of wild-type mice with Nrp1-depleted bone marrow-derived macrophages (BMDM) confers resistance to the development of glioma. This resistance occurred in a similar fashion seen in mice in which all macrophages lacked Nrp1 expression. Tumors had decreased volumes, decreased vascularity, increased CTL infiltrate, and Nrp1-depleted BMDM adopted a more antitumorigenic phenotype relative to wild-type GAMs within the tumors. Mice with Nrp1-deficient microglia and wild-type peripheral macrophages showed resistance to glioma development and had higher microglial infiltrate than mice with wild-type GAMs. Our findings show how manipulating Nrp1 in either peripheral macrophages or microglia reprograms their phenotype and their pathogenic roles in tumor neovascularization and immunosuppression.Significance: This study highlights the proangiogenic receptor neuropilin 1 in macrophages and microglial cells in gliomas as a pivotal modifier of tumor neovascularization and immunosuppression, strengthening emerging evidence of the functional coordination of these two fundamental traits of cancer. Cancer Res; 78(3); 685-94. ©2017 AACR.


Assuntos
Medula Óssea/patologia , Neoplasias Encefálicas/prevenção & controle , Glioma/prevenção & controle , Macrófagos/patologia , Microglia/patologia , Neuropilina-1/fisiologia , Animais , Medula Óssea/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Células Cultivadas , Progressão da Doença , Feminino , Glioma/genética , Glioma/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Deleção de Sequência
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