Macropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer

Recouvreux, M. Victoria; Commisso, Cosimo

doi:10.3389/fendo.2017.00261

Cited by 178 publications

(184 citation statements)

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“…Multiple proteins and signalling factors are involved in macropinocytosis, including the Rho superfamily of GTPases (Rac, Cdc42), lipid components (phosphoinositides, cholesterol, phosphatidylinositol phosphates), phospholipid kinases, receptor tyrosine kinases and phosphatases, SNX‐5 and DKK‐3 . There is also large body of evidence that now shows macropinocytosis can be specifically activated by extracellular stimuli, such as growth factors and natural or synthetic chemicals, and the activated macropinocytosis can have effects on cell survival/proliferation or cell death/growth inhibition on distinct cell types including cancer cells …”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15][16] There is also large body of evidence that now shows macropinocytosis can be specifically activated by extracellular stimuli, such as growth factors and natural or synthetic chemicals, and the activated macropinocytosis can have effects on cell survival/proliferation or cell death/growth inhibition on distinct cell types including cancer cells. 17,18 Meridianin C is one of the marine derived indole alkaloids (meridianin A-G) isolated from the South Atlantic tunicate Aplidium meridianum. 19,20 Previously, meridianin C, D or G analogues/derivatives have been shown to inhibit the proliferation of human breast (MCF-7) and cervix (HeLa) cancer and leukaemia (MV4-11) cells.…”

Section: Introductionmentioning

confidence: 99%

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Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

Park

Mahesh

et al. 2018

J Cellular Molecular Medi

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Meridianin C is a marine natural product known for its anti‐cancer activity. At present, the anti‐tumour effects of meridianin C on oral squamous cell carcinoma are unknown. Here, we investigated the effect of meridianin C on the proliferation of four different human tongue cancer cells, YD‐8, YD‐10B, YD‐38 and HSC‐3. Among the cells tested, meridianin C most strongly reduced the growth of YD‐10B cells; the most aggressive and tumorigenic of the cell lines tested. Strikingly, meridianin C induced a significant accumulation of macropinosomes in the YD‐10B cells; confirmed by the microscopic and TEM analysis as well as the entry of FITC‐dextran, which was sensitive to the macropinocytosis inhibitor amiloride. SEM data also revealed abundant long and thin membrane extensions that resemble lamellipodia on the surface of YD‐10B cells treated with meridianin C, pointing out that meridianin C‐induced macropinosomes was the result of macropinocytosis. In addition, meridianin C reduced cellular levels of Dickkopf‐related protein‐3 (DKK‐3), a known negative regulator of macropinocytosis. A role for DKK‐3 in regulating macropinocytosis in the YD‐10B cells was confirmed by siRNA knockdown of endogenous DKK‐3, which led to a partial accumulation of vacuoles and a reduction in cell proliferation, and by exogenous DKK‐3 overexpression, which resulted in a considerable inhibition of the meridianin C‐induced vacuole formation and decrease in cell survival. In summary, this is the first study reporting meridianin C has novel anti‐proliferative effects via macropinocytosis in the highly tumorigenic YD‐10B cell line and the effects are mediated in part through down‐regulation of DKK‐3.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

Park

Mahesh

et al. 2018

J Cellular Molecular Medi

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“…Several studies demonstrated that macropinocytosis, through uptake of extracellular proteins (e.g. albumin) and their further degradation in lysosomes, enables cancer cells to survive in a nutrient-poor tumor microenvironment (Commisso et al, 2013;Lee et al, 2019;Palm, 2019;Recouvreux & Commisso, 2017). However, the majority of these studies concentrated on macropinocytosis triggered by mutated RAS and/or were conducted in pancreatic cancer cells, whereas data on RTK-mediated macropinocytosis as an alternative nutrient uptake route in other cancer types were lacking.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that pancreatic cancer cells expressing oncogenic RAS upregulate macropinocytosis to acquire extracellular albumin which, upon lysosomal degradation, provides amino acids for the metabolism and cell growth. In this way, macropinocytosis allows cancer cells to survive in a nutrient-poor tumor microenvironment (Commisso et al, 2013;Palm, 2019;Recouvreux & Commisso, 2017).…”

Section: Introductionmentioning

confidence: 99%

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

Zdżalik-Bielecka

Poświata

Kozik

et al. 2020

Preprint

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AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand GAS6 are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6induced CDRs contributed to focal adhesion (FA) turnover, cell spreading and elongation.Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model.All these processes required the kinase activity of AXL but not TYRO3, and downstream activation of PI3K. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements and macropinocytosis that jointly contribute to cancer cell invasion.

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“…Additionally the metabolic stress conditions were found to increase the membrane ruffling and formation of actin rich macropinocytosis. Abundance of macropinocytes or cytoneme like structure in stressed spheroids might control the entosis or nutrient-scavenging mechanisms to support the tumorogenesis within the nutrient-deprived environments 48 .…”

Section: Discussionmentioning

confidence: 99%

Nutritional stress alone can controlin vitrotumor formation and its invasive nature

Gayan

Teli

Nair

et al. 2020

Preprint

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The metastatic nature is an inherent property of the tumor. However, the effect of the environmental stress conditions on tumor microcosm in the context of metastasis needs to be analyzed. This work is proposed to analyze the tumor behavior under multiple metabolic stress conditions, such as deprivation of glucose, protein, and oxygen. The spheroid proliferation rate is observed to be influenced profoundly by the stress level where minimal stress produces compact spheroid and severe stress make unstable aggregate like structures. It is observed that the non-invasive cancer cells cannot form spheroids under extreme stress.Stress conditions influence the mRNA levels of hypoxic, angiogenic and ECM deformation specific gene cluster. Spheroid reversal assay reveals the quiescent nature of the stressed spheroids under continuous stress conditions. However, after the rescue, the stressed spheroids were found to opt for different migration modalities. Extremely stressed noninvasive spheroids display atypical sprout-like growth within the invasion matrix and severely stressed spheroids can control the migration pattern of mesenchymal stem cells.Thus, it is concluded that multiple nutritional stress influence the spheroid formation and physiology along with the conversion of a non-invasive spheroids into quasi-invasive one. Introduction: Introduction:Cancer is one of the most fatal diseases due to its metastatic behavior. Tumors (>2-5 cm diameter) with a necrotic core, and a proliferating periphery initiate the shedding of metastatic cells and instigate the growth of occult tumors in other tissues 1 . Migration of tumor cells towards the greener pasture of future metastatic niches is a complex process.Therefore, understanding of metastasis at a molecular level has gathered much interest, because of its potential to provide much deeper insight into the tumor's social intelligence and probable cure 2 . Many factors such as tumor microenvironment, extra cellular matrix and the environmental stress are presumed to influence metastasis 3, 4 . Additionally inter-cellular conditions like deprivation of nutrition and oxygen are assumed to play influential role in angiogenesis and aggression of the tumor 5, 6 . Rapidly growing tumors utilize the available glucose inefficiently and initiate acidosis 7, 8 . Experimental deprivation of glucose is found to induce cell death in vitro while in xenograft studies it has been found to activate AMPK and ATF4 pathways to initiate angiogenesis 9, 10 . Similarly protein or amino acid (such as arginine) starvation induces apoptosis which can be bypassed through the GCN2/ATF4 Pathway 11, 12 . Hypoxic stress in cell culture condition induces apoptotic cell death and plays an important role in autophagy [13][14][15] . However in tumors hypoxic stress has also been highlighted as one of the most important factor to initiate angiogenesis and metastasis 16,17 . In fact, this multifaceted relationship between angiogenesis and metastasis seems to be synergistic in nature, as anti-angiogenic therapies ha...

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Macropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer

Cited by 178 publications

References 71 publications

Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

Nutritional stress alone can controlin vitrotumor formation and its invasive nature

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