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Lysosomes and autophagy in cell death control

Key Points

  • Lysosomes contain catabolic hydrolases that participate in the digestion of autophagic material (after fusion between lysosomes and autophagosomes), in acute cell death (after lysosomal-membrane permeabilization, LMP) or in tissue invasion (after their release into the extracellular space).

  • LMP can be induced by classic apoptotic stimuli, intracellular second messengers such as reactive oxygen species and sphingosine, as well as by lysosomotropic toxins. Often, LMP causes mitochondrial outer-membrane permeabilization and caspase activation, which are two of the hallmarks of apoptosis.

  • Lysosomal alterations are common in cancer cells in which increased expression of lysosomal enzymes participates in tissue invasion and tumour growth, yet overexpressed heat-shock protein 70 (HSP70) locally prevents LMP. Targeting of lysosomes by lysosomotropic toxins, inhibitors of the vacuolar H+-ATPase or downmodulation/inhibition of HSP70 might have cancer-selective cytotoxic effects.

  • The autophagic sequestration of parts of the cytosol and/or cytoplasmic organelles is involved in the cellular adaptation to nutrient deprivation and sub-lethal damage. Therefore, autophagy might prevent cell death under some conditions. However, in some instances, particularly when apoptosis is inhibited, high levels of autophagy can function as a cell death effector mechanism.

  • Defective autophagy might participate in carcinogenesis, possibly owing to a reduced removal of defective organelles and/or damaged cells. Some chemotherapeutic agents can induce morphological changes, which indicate that autophagic cell death is occurring in the treated cells, but there is no formal proof that this type of cell death is involved in endogenous or therapeutic tumour suppression.

  • Specific therapeutic strategies might exploit the structural and functional abnormalities that affect the lysosomal and autophagic compartments in cancer cells.

Abstract

Lysosomal hydrolases participate in the digestion of endocytosed and autophagocytosed material inside the lysosomal/autolysosomal compartment in acute cell death when released into the cytosol and in cancer progression following their release into the extracellular space. Lysosomal alterations are common in cancer cells. The increased expression and altered trafficking of lysosomal enzymes participates in tissue invasion, angiogenesis and sensitization to the lysosomal death pathway. But lysosomal heat-shock protein 70 locally prevents lysosomal-membrane permeabilization. Similarly, alterations in the autophagic compartment are linked to carcinogenesis and resistance to chemotherapy. Targeting these pathways might constitute a novel approach to cancer therapy.

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Figure 1: Lysosomal-membrane permeabilization-inducers and consequences.
Figure 2: Lysosomes in normal versus cancer cells.
Figure 3: Autophagy as a cytoprotective mechanism.
Figure 4: Autophagy as a cell death mechanism.
Figure 5: Relationship between apoptosis and autophagic cell death.

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Acknowledgements

G.K. is supported by the Ligue Nationale contre le Cancer and the European Union. M.J. is supported by the Danish Cancer Society, the Danish National Research Foundation, the Danish Medical Research Council and the Association for International Cancer Research.

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Correspondence to Guido Kroemer or Marja Jäättelä.

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DATABASES

Entrez Gene

ASM

BAK

BAX

Bcl2

BCL-XL

BECN1

BID

caspase 8

cathepsin B

cathepsin D

cathepsin L

cystatin A

cystatin B

FAN

HSP70-1

LIMK1

mTOR

NSM

p53

RAS

RHOA

RIP1

ROCK

TNF

TNFR1

TRAIL

Glossary

CASPASES

A family of cysteine proteases that cleave after asparagine residues. Initiator caspases (for example, caspase 8) are typically activated in response to particular stimuli, whereas effector caspases (such as caspase 3) are important for the ordered dismantling of vital cellular structures.

MITOCHONDRIAL OUTER-MEMBRANE PERMEABILIZATION

An apoptosis-associated process that results in the release of apoptosis-inducing proteins, which are normally retained in the mitochondrial intermembrane space, through the outer membrane and into the cytosol.

CATHEPSINS

Proteases that locate mostly to lysosomes and lysosome-like organelles.

AUTOPHAGY

In this review, autophagy is used synonymous to macro-autophagy, a process in which a portion of the cytoplasm is wrapped into a specific membrane and later digested by lysosomal enzymes.

LYSOSOMAL-MEMBRANE PERMEABILIZATION

A perturbation of lysosomal membrane function that leads to the translocation of lysosomal hydrolases (including cathepsins) from the lysosomal lumen to the rest of the cell. LMP can be induced by endogenous signal transducers (such as reactive oxygen species and sphingosine) as well as by lysosomotropic drugs.

PROGRAMMED CELL DEATH

An active cell death process that can be blocked by inhibition of a signal or activity within the target cell.

DEATH RECEPTORS

A family of cell-surface receptors that are capable of mediating cell death on ligand-induced trimerization. The best-studied members include tumour-necrosis factor receptor 1 (TNFR1), FAS (also known as CD95), and the two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and TRAILR2).

REACTIVE OXYGEN SPECIES

Collective term comprising classic oxygen radicals and peroxides that are formed inside the cell.

Bcl2 FAMILY

Proteins that contain at least one BCL2 homology (BH) region. The family is divided into anti-apoptotic proteins (such as BCL2 and BCL-XL) that contain four BH domains (BH1, BH2, BH3 and BH4), pro-apoptotic proteins (for example, BAX and BAK) that contain BH1, BH2 and BH3, and the pro-apoptotic BH3-only proteins.

CYTOCHROME C

A haem protein that is normally confined to the mitochondrial intermembrane space. On induction of apoptosis, cytochrome c is released from mitochondria and triggers the formation of the apoptosome, a caspase-activation complex.

FENTON-TYPE CHEMISTRY

The Fenton reaction is the formation of OH, OH and Fe3+ from the non-enzymatic reaction of Fe2+ with H2O2; an important reaction in the oxidative stress of blood cells and various tissues.

Rab GTPASES

Monomeric, small GTPases that, together with their effectors, mediate the first event during membrane fusion — the tethering of vesicles to each other or to other membranes.

SIGMA-2 RECEPTOR

Sigma receptors (1 and 2) are orphan receptors that bind psychoactive substances and modulate neuronal function and cancer cell survival.

AMPHISOME

A vesicle formed by fusion of an autophagosome with an endosome.

AUTOLYSOSOME

Also called autophagolysosome. A vesicle formed by the fusion of an autophagosome (or an amphisome) with a lysosome.

CHEDIAK–HIGASHI SYNDROME

A rare autosomal-recessive genetic disorder caused by mutations in CHS1 (which is involved in lysosomal fission and secretion).

GRISCELLI SYNDROME TYPE 2

A rare autosomal-recessive genetic disorder caused by mutations in RAB27A (which is involved in the movement of secretory lysosomes).

APOPTOSIS-INDUCING FACTOR

(AIF). A flavoprotein that is normally present in the mitochondrial intermembrane space. On induction of apoptosis, AIF translocates to the nucleus where it activates a molecular complex that causes large-scale DNA fragmentation, presumably in a caspase-independent fashion.

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Kroemer, G., Jäättelä, M. Lysosomes and autophagy in cell death control. Nat Rev Cancer 5, 886–897 (2005). https://doi.org/10.1038/nrc1738

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