Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

Su, Hua; Yang, Fei; Fu, Rao; Li, Xin; French, Randall; Mose, Evangeline; Pu, Xiaohong; Trinh, Brittney; Kumar, Avi; Liu, Junlai; Antonucci, Laura; Todoric, Jelena; Liu, Yuan; Hu, Yinling; Diaz‐Meco, María T.; Moscat, Jorge; Metallo, Christian M.; Lowy, Andrew M.; Sun, Beicheng; Karin, Michael

doi:10.1016/j.ccell.2021.02.016

Cited by 99 publications

(69 citation statements)

References 65 publications

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“…Ruffling of cholesterol-rich membrane microdomains leads to the unselective incorporation of large volumes of extracellular fluid in macropinosomes with a diameter of 0.2 up to 5.0 μm ( Levin et al, 2015 ; Donaldson, 2019 ). Macropinocytosis may occur constitutively or be induced by growth factors, chemokines, microbial products, viruses ( Freeman et al, 2014 ; Marques et al, 2017 ; Canton, 2018 ; Doodnauth et al, 2019 ; Tejeda-Munoz et al, 2019 ), crosslinking of cell surface molecules ( Imamura et al, 2011 ), knockdown of genes ( Choi et al, 2017 ; Fomin et al, 2018 ; Fomin, 2019 ; Su et al, 2021 ), and constitutive expression ( Kasahara et al, 2007 ) or mutations of signal transduction molecules ( Yoo et al, 2020 ). Some cells, like innate immune cells and Ras-transformed cancer cells, are able to perform both forms of macropinocytosis ( Amyere et al, 2000 ; Stow et al, 2020 ).…”

Section: Macropinocytosismentioning

confidence: 99%

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From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Ritter

Bresgen

Kerschbaum

2021

Front. Cell Dev. Biol.

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The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.

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Section: Macropinocytosismentioning

confidence: 99%

“…Recently, it has been shown that dual inhibition of autophagy and macropinocytosis is a successful strategy in treating mice with pancreatic ductal adenocarcinomas. Advancing this strategy to clinical applications may be promising for cancer therapy ( Staff, 2021 ; Su et al, 2021 ).…”

Section: Perspectivesmentioning

confidence: 99%

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Ritter

Bresgen

Kerschbaum

2021

Front. Cell Dev. Biol.

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“…To maintain tumor cell viability and survival, oncogenic KRAS induces autophagy, a lysosome-mediated process whereby cells degrade organelles and macromolecules, with the resulting breakdown products subsequently utilized as metabolic intermediates [39]. Furthermore, oncogenic KRAS promotes macropinocytosis to transport extracellular proteins as an amino acid source for the TCA cycle to sustain tumor growth [40]. The autophagy-to-macropinocytosis switch depends on NRF2-mediated induction of macropinocytosis components.…”

Section: Kras Dependency and Metabolismmentioning

confidence: 99%

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Abe

Kimura

Hirade

et al. 2021

Cancers

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Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

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“…However, ULK1 inhibitors alone are not sufficient for tumor suppression in certain cancers. Recently, a paper was published explaining the reason why the anticancer effect of ULK inhibition monotherapy was ineffective in pancreatic ductal adenocarcinoma (PDAC) [ 68 ]. Intriguingly, autophagy inhibition induced micropinocytosis, which is the uptake of extracellular fluid droplets containing proteins and other macromolecules.…”

Section: Modulators Of Initial Autophagy and Cancer Treatmentmentioning

confidence: 99%

Autophagy Modulators in Cancer: Focus on Cancer Treatment

Nam

2021

Life

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Uncontrolled autophagy has been associated with the development and progression of various cancers that are resistant to cancer therapy. Therefore, many efforts to modulate uncontrolled autophagy as a cancer treatment have been attempted, from basic science to clinical trials. However, it remains difficult to equally apply autophagy modulators to cancer therapy because autophagy is a double-edged sword in cancer: it can be tumor-suppressive or tumor-protective. Therefore, the precise mechanisms of autophagy modulators and their varied responsiveness to each cancer type should be addressed in detail. This study will describe the precise mechanisms of developing various autophagy modulators, their current therapeutic applications and future perspectives.

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Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

Cited by 99 publications

References 65 publications

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Autophagy Modulators in Cancer: Focus on Cancer Treatment

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