Macropinocytosis contributes to the macrophage foam cell formation in RAW264.7 cells

Yao, Wenqi; Li, Ké; Liao, Kan

doi:10.1093/abbs/gmp066

Cited by 29 publications

(25 citation statements)

References 34 publications

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“…To explain the above studies, we hypothesized that VPA interacted with DOX and formed a particle or complex chemical-like structure, which might be the cause of increased DOX internalization. Thus, we evaluated different cellular surface receptor-mediated pathways: the clathrin-, caveolae-, and macropinocytosis-mediated DOX internalization pathways [47,70,71]. As expected, we observed that DOX internalization increased drastically in the VPA-DOX combination group compared with that in the free DOX group (see Figure 5A–C).…”

Section: Discussionsupporting

confidence: 54%

“…To investigate the endocytosis pathway, the cells were cultured at different temperatures (37, 25 and 4 °C) in the presence of DOX (1 μM) or the VPA and DOX combination (DOX concentration, 1 μM) for 3 h. It has been established that the incubation of cells at 4 °C could block endocytosis [50]. Concurrently, cells were pre-treated for 1 h with various kinds of specific endocytosis inhibitors: CPZ (10 μM), an inhibitor of clathrin-mediated endocytosis [80]; MβCD (3 mM), an inhibitor of caveolae-mediated endocytosis [80]; and LY (20 μM), an inhibitor of macropinocytosis [71]. After incubation for 3 h with DOX or the VPA and DOX combination, the cells were washed twice with PBS and the fluorescent intensity of DOX in the cells was evaluated using the fluorescence microplate reader (GeminiEM) with excitation and emission wavelengths of approximately 470 and 570 nm, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

Saha

Yin

Kim

et al. 2017

IJMS

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Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

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Section: Discussionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

Saha

Yin

Kim

et al. 2017

IJMS

View full text Add to dashboard Cite

show abstract

“…To explain the above studies, we hypothesized that VPA interacted with DOX and formed a particle or complex chemical-like structure, which might be the cause of increased DOX internalization. Thus, we evaluated different cellular surface receptor-mediated pathways: the clathrin-, caveolae-, and macropinocytosis-mediated DOX internalization pathways [25,45,46]. As expected, we observed that DOX internalization increased drastically in the VPA-DOX combination group compared with that in the free DOX group (see Figures 5 A-C).…”

Section: Discussionsupporting

confidence: 63%

“…To investigate the endocytosis pathway, the cells were cultured at different temperatures (37 °C, 25 °C, and 4 °C) in the presence of DOX (1 μM) or the VPA and DOX combination (DOX concentration, 1 μM) for 3 h. It has been established that the incubation of cells at 4 °C could block endocytosis [28]. Concurrently, cells were pre-treated for 1 h with various kinds of specific endocytosis inhibitors: CPZ (10 μM), an inhibitor of clathrin-mediated endocytosis [51]; MβCD (3 mM), an inhibitor of caveolae-mediated endocytosis [51]; and LY (20 μM), an inhibitor of macropinocytosis [46]. After incubation for 3 h with DOX or the VPA and DOX combination, the cells were washed twice with PBS and the fluorescent intensity of DOX in the cells was evaluated using the fluorescence microplate reader (GeminiEM) with excitation and emission wavelengths of approximately 470 nm and 570 nm, respectively.…”

Section: Determination Of the Endocytosis Pathwaysmentioning

confidence: 99%

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Anti-Proliferation Effects in Hepatocellular Carcinoma Cells

Saha¹,

Yin²,

Kim³

et al. 2017

Preprint

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Abstract:We evaluated the mono-and combination-therapy effects of valproic acid (VPA) and doxorubicin (DOX) in hepatocellular carcinoma (HCC) and identified a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

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“…To the extent that it is desirable to inhibit macrophage accumulation of cholesterol in atherosclerotic plaques, it will be necessary to pharmacologically target fluid-phase pinocytosis in plaques. Macrophage fluid-phase macropinocytosis of LDL depends on Rho GTPase and PI3-kinase function [18•, 28•, 29, 59] suggesting that these are useful signaling molecules to target for inhibition. On the other hand, stimulating fluid-phase pinocytosis of LDL in organs such as the spleen and liver potentially provides a new approach to lowering plasma cholesterol levels.…”

Section: Resultsmentioning

confidence: 99%

Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles

Kruth

2011

Current Opinion in Lipidology

108

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Purpose of review Because early findings indicated that native low density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in vitro incubations, investigators presumed that LDL must be modified in some way to trigger its uptake by the macrophage. The purpose of this review is to discuss recent findings showing that native unmodified LDL can induce massive macrophage cholesterol accumulation mimicking macrophage foam cell formation that occurs within atherosclerotic plaques. Recent findings Macrophages that show high rates of fluid-phase pinocytosis also show similar high rates of uptake of native unmodified LDL through non-receptor mediated uptake within both macropinosomes and micropinosomes. Non-saturable fluid-phase uptake of LDL by macrophages converts the macrophages into foam cells. Different macrophage phenotypes demonstrate either constitutive fluid-phase pinocytosis or inducible fluid-phase pinocytosis. Fluid-phase pinocytosis has been demonstrated by macrophages within mouse atherosclerotic plaques indicating that this pathway contributes to plaque macrophage cholesterol accumulation. Summary Contrary to what has been believed previously, macrophages can take up large amounts of native unmodified LDL by receptor-independent, fluid-phase pinocytosis converting these macrophages into foam cells. Thus, targeting macrophage fluid-phase pinocytosis should be considered when investigating strategies to limit macrophage cholesterol accumulation in atherosclerotic plaques.

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Macropinocytosis contributes to the macrophage foam cell formation in RAW264.7 cells

Cited by 29 publications

References 34 publications

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Anti-Proliferation Effects in Hepatocellular Carcinoma Cells

Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles

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