Abstract
Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.
Keywords
- Macropinocytosis
- Cell metabolism
- Nutrient uptake
- Stress stimuli
- Nutrient scarcity
- Cancer malignancy
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References
Ackerman D et al (2018) Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Rep 24(10):2596–2605 e5
Agani F, Jiang BH (2013) Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets 13(3):245–251
Anthony JC et al (2001) Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr 131(3):856S–860S
Araki N, Johnson MT, Swanson JA (1996) A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol 135(5):1249–1260
Araki N et al (2007) Phosphoinositide metabolism during membrane ruffling and macropinosome formation in EGF-stimulated A431 cells. Exp Cell Res 313(7):1496–1507
Ard R et al (2015) Regulation of macropinocytosis by diacylglycerol kinase zeta. PLoS One 10(12):e0144942
Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120(4):483–495
Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313
Bloomfield G, Kay RR (2016) Uses and abuses of macropinocytosis. J Cell Sci 129(14):2697–2705
Bohdanowicz M et al (2013) Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes. Mol Biol Cell 24(11):1700–1712, S1-7
Bryant DM et al (2007) EGF induces macropinocytosis and SNX1-modulated recycling of E-cadherin. J Cell Sci 120(Pt 10):1818–1828
Canton J et al (2016) Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages. Nat Commun 7:11284
Cao Y et al (2019) Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell Int 19:254
Cepeda EB et al (2015) Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells. Biochim Biophys Acta 1853(5):1205–1218
Chen Q et al (2018) Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab 27(5):1007–1025 e5
Choi YH (2018) ROS-mediated activation of AMPK plays a critical role in sulforaphane-induced apoptosis and mitotic arrest in AGS human gastric cancer cells. Gen Physiol Biophys 37(2):129–140
Choi SH et al (2009) Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ Res 104(12):1355–1363
Colavitti R, Finkel T (2005) Reactive oxygen species as mediators of cellular senescence. IUBMB Life 57(4–5):277–281
Commisso C, Debnath J (2018) Macropinocytosis fuels prostate cancer. Cancer Discov 8(7):800–802
Commisso C et al (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497(7451):633–637
Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34(12):620–627
Davidson SM, Vander Heiden MG (2017) Critical functions of the lysosome in cancer biology. Annu Rev Pharmacol Toxicol 57:481–507
Davidson SM et al (2017) Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med 23(2):235–241
Daye D, Wellen KE (2012) Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 23(4):362–369
Dharmawardhane S et al (2000) Regulation of macropinocytosis by p21-activated kinase-1. Mol Biol Cell 11(10):3341–3352
Djordjevic T et al (2005) The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med 38(5):616–630
Donaldson JG, Porat-Shliom N, Cohen LA (2009) Clathrin-independent endocytosis: a unique platform for cell signaling and PM remodeling. Cell Signal 21(1):1–6
Farnsworth RH et al (2014) Vascular remodeling in cancer. Oncogene 33(27):3496–3505
Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156
Fujii M et al (2013) Dissecting the roles of Rac1 activation and deactivation in macropinocytosis using microscopic photo-manipulation. Sci Rep 3:2385
Garcia D, Shaw RJ (2017) AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66(6):789–800
Ghoshal P et al (2017) Nox2-mediated PI3K and cofilin activation confers alternate redox control of macrophage pinocytosis. Antioxid Redox Signal 26(16):902–916
Gu Z et al (2011) Integrins traffic rapidly via circular dorsal ruffles and macropinocytosis during stimulated cell migration. J Cell Biol 193(1):61–70
Gullino PM, Grantham FH, Courtney AH (1967) Glucose consumption by transplanted tumors in vivo. Cancer Res 27(6):1031–1040
Gwinn DM et al (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226
Hawkins KE et al (2016) NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming. Cell Rep 14(8):1883–1891
Hess D, Chisholm JW, Igal RA (2010) Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS One 5(6):e11394
Hinchy EC et al (2018) Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J Biol Chem 293(44):17208–17217
Hobbs GA, Der CJ, Rossman KL (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129(7):1287–1292
Hobbs GA et al (2020) Atypical KRAS(G12R) mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov 10(1):104–123
Hodakoski C et al (2019) Rac-mediated macropinocytosis of extracellular protein promotes glucose independence in non-small cell lung cancer. Cancers (Basel) 11(1)
Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590
Jayashankar V, Edinger AL (2020) Macropinocytosis confers resistance to therapies targeting cancer anabolism. Nat Commun 11(1):1121
Jewell JL, Guan KL (2013) Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38(5):233–242
Kamphorst JJ et al (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A 110(22):8882–8887
Kamphorst JJ et al (2015) Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75(3):544–553
Karasic TB et al (2019) Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol 5(7):993–998
Karna E et al (2020) Proline-dependent regulation of collagen metabolism. Cell Mol Life Sci 77(10):1911–1918
Karsli-Uzunbas G et al (2014) Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 4(8):914–927
Kasahara K et al (2007) Role of Src-family kinases in formation and trafficking of macropinosomes. J Cell Physiol 211(1):220–232
Keith B, Johnson RS, Simon MC (2011) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12(1):9–22
Kim SM et al (2018) PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells. Cancer Discov 8(7):866–883
King B et al (2020) Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis. Genes Dev 34(19–20):1345–1358
Kondratowicz AS et al (2013) AMP-activated protein kinase is required for the macropinocytic internalization of ebolavirus. J Virol 87(2):746–755
Koong AC, Chen EY, Giaccia AJ (1994) Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res 54(6):1425–1430
Kuper A et al (2021) Overcoming hypoxia-induced resistance of pancreatic and lung tumor cells by disrupting the PERK-NRF2-HIF-axis. Cell Death Dis 12(1):82
Lee P, Chandel NS, Simon MC (2020) Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol 21(5):268–283
Lee SW et al (2019) EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis. Dev Cell 50(3):381–392 e5
Li H et al (2019) Role of Nrf2 in the antioxidation and oxidative stress induced developmental toxicity of honokiol in zebrafish. Toxicol Appl Pharmacol 373:48–61
Liberali P et al (2008) The closure of Pak1-dependent macropinosomes requires the phosphorylation of CtBP1/BARS. EMBO J 27(7):970–981
Liu Z, Roche PA (2015) Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells. Front Physiol 6:1
Liu W et al (2012) Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci U S A 109(23):8983–8988
Luo W et al (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426
Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318
Melander MC et al (2015) The collagen receptor uPARAP/Endo180 in tissue degradation and cancer (Review). Int J Oncol 47(4):1177–1188
Mercer J, Helenius A (2009) Virus entry by macropinocytosis. Nat Cell Biol 11(5):510–520
Merlot AM, Kalinowski DS, Richardson DR (2014) Unraveling the mysteries of serum albumin-more than just a serum protein. Front Physiol 5:299
Michalopoulou E et al (2020) Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition. Cell Rep 30(8):2729–2742 e4
Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741
Moser TS et al (2010) A kinome RNAi screen identified AMPK as promoting poxvirus entry through the control of actin dynamics. PLoS Pathog 6(6):e1000954
Muz B et al (2015) The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 3:83–92
Nakase I et al (2015) Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci Rep 5:10300
Navale AM, Paranjape AN (2016) Glucose transporters: physiological and pathological roles. Biophys Rev 8(1):5–9
Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295
Nofal M et al (2017) mTOR inhibition restores amino acid balance in cells dependent on catabolism of extracellular protein. Mol Cell 67(6):936–946 e5
Oh ET et al (2016) NQO1 inhibits proteasome-mediated degradation of HIF-1alpha. Nat Commun 7:13593
Olivares O et al (2017) Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun 8:16031
Onodera J, Ohsumi Y (2005) Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J Biol Chem 280(36):31582–31586
Palm W (2019) Metabolic functions of macropinocytosis. Philos Trans R Soc Lond B Biol Sci 374(1765):20180285
Palm W et al (2015) The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162(2):259–270
Palm W et al (2017) Critical role for PI3-kinase in regulating the use of proteins as an amino acid source. Proc Natl Acad Sci U S A 114(41):E8628–E8636
Pizzimenti S et al (2010) The “two-faced” effects of reactive oxygen species and the lipid peroxidation product 4-hydroxynonenal in the hallmarks of cancer. Cancers (Basel) 2(2):338–363
Qian Y et al (2014) Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett 351(2):242–251
Racoosin EL, Swanson JA (1989) Macrophage colony-stimulating factor (rM-CSF) stimulates pinocytosis in bone marrow-derived macrophages. J Exp Med 170(5):1635–1648
Racoosin EL, Swanson JA (1993) Macropinosome maturation and fusion with tubular lysosomes in macrophages. J Cell Biol 121(5):1011–1020
Recouvreux MV, Commisso C (2017) Macropinocytosis: a metabolic adaptation to nutrient stress in cancer. Front Endocrinol (Lausanne) 8:261
Redelman-Sidi G et al (2018) The canonical Wnt pathway drives macropinocytosis in cancer. Cancer Res 78(16):4658–4670
Ridley AJ et al (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70(3):401–410
Sarbassov DD et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169(2):361–371
Schmees C et al (2012) Macropinocytosis of the PDGF beta-receptor promotes fibroblast transformation by H-RasG12V. Mol Biol Cell 23(13):2571–2582
Schrader M, Fahimi HD (2004) Mammalian peroxisomes and reactive oxygen species. Histochem Cell Biol 122(4):383–393
Seguin L et al (2017) Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov 7(12):1464–1479
Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123(9):3664–3671
Shaw RJ (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196(1):65–80
Singla B et al (2018) PKCdelta-mediated Nox2 activation promotes fluid-phase pinocytosis of antigens by immature dendritic cells. Front Immunol 9:537
Su H et al (2021) Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell
Swanson JA (2008) Shaping cups into phagosomes and macropinosomes. Nat Rev Mol Cell Biol 9(8):639–649
Tao S et al (2019) Correction: oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res 79(5):1015
Thompson CB (2011) Rethinking the regulation of cellular metabolism. Cold Spring Harb Symp Quant Biol 76:23–29
Topham MK, Prescott SM (2001) Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism. J Cell Biol 152(6):1135–1143
Toth RK, Warfel NA, Bedfellows S (2017) Nuclear factor, erythroid 2-like 2 (Nrf2) and hypoxia-inducible factor 1 (HIF-1) in tumor hypoxia. Antioxidants (Basel) 6(2)
Urasaki Y, Heath L, Xu CW (2012) Coupling of glucose deprivation with impaired histone H2B monoubiquitination in tumors. PLoS One 7(5):e36775
Veithen A et al (1996) v-Src induces constitutive macropinocytosis in rat fibroblasts. J Cell Sci 109(Pt 8):2005–2012
Wang X, Proud CG (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21:362–369
Waters AM, Der CJ (2018) KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med 8(9)
Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370
Wennstrom S et al (1994) Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling. Curr Biol 4(5):385–393
West MA, Bretscher MS, Watts C (1989) Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells. J Cell Biol 109(6 Pt 1):2731–2739
Westphalen CB, Olive KP (2012) Genetically engineered mouse models of pancreatic cancer. Cancer J 18(6):502–510
Yoshida S et al (2015) Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. J Cell Biol 211(1):159–172
Yoshida S et al (2018) Macropinocytosis, mTORC1 and cellular growth control. Cell Mol Life Sci 75(7):1227–1239
Yue S et al (2014) Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 19(3):393–406
Zhang Y et al (2021) Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness. Cancer Discov
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Lambies, G., Commisso, C. (2022). Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways. In: Commisso, C. (eds) Macropinocytosis. Subcellular Biochemistry, vol 98. Springer, Cham. https://doi.org/10.1007/978-3-030-94004-1_2
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