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How melanoma cells evade trail-induced apoptosis

Key Points

  • Several natural defence mechanisms kill melanoma cells by apoptosis. These are induced by granzyme B or interaction with members of the tumour necrosis factor (TNF) family, such as TNF-related apoptosis-inducing ligand (TRAIL).

  • As a consequence, melanoma cells that survive in the host might do so because they have been selected for resistance to apoptosis. Resistance mechanisms include low death-receptor expression and inhibition of intracellular death pathways.

  • Induction of p53 is important in upregulation of TRAIL death receptors in response to DNA damage, but relatively little is known about the control of constitutive expression. Fresh isolates of melanoma cells have low death-receptor expression and development of treatments that increase their expression are crucial for the success of TRAIL-dependent killing of melanoma.

  • One of the main inhibitors of TRAIL-induced apoptosis is the inhibitors of apoptosis (IAP) family, particularly XIAP. XIAP levels are reduced after exposure to TRAIL because TRAIL induces release of a pro-apoptotic protein, SMAC/DIABLO, from mitochondria, which binds to and inactivates members of the IAP family. This represents an alternative to the classical mitochondrial death pathway, which is limited in most melanoma cells by low or absent APAF1 levels.

  • SMAC/DIABLO release from the mitochondria of TRAIL-resistant melanoma cells is decreased, possibly due to stabilization of mitochondrial permeability by the BCL2 family.

  • The transcription factor NF-κB and the mitogen-activated protein kinase (MAPK) and extracellular-regulated kinase (ERK) 1 and 2 pathways seem to be the principal regulators of the IAP and BCL2 family, respectively.

  • These findings provide insights into resistance of melanoma to apoptosis and provide a framework for therapeutic approaches based on providing pro-apoptotic stimuli, as well as reducing anti-apoptotic mechanisms.

Abstract

At the doses used clinically, chemotherapy is believed to kill melanoma by a final common 'mitochondrial' pathway that leads to apoptosis. Similarly, several natural defence mechanisms kill melanoma by the same pathways. A corollary to the latter is that survival of melanoma in the host is due to the development of anti-apoptotic mechanisms in melanoma cells. What are these mechanisms? And how might we bypass them to improve the treatment of melanoma?

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Figure 1: The 'classical' intrinsic mitochondrial pathway to apoptosis.
Figure 2: Involvement of the mitochondrial pathway in target-cell killing by CTLs or NK cells.
Figure 3: The 'classical' extrinsic signalling pathway suggested for TRAIL-induced apoptosis.
Figure 4: The alternative mitochondrial pathway to apoptosis used by TRAIL.
Figure 5: NF-κB induces a number of anti-apoptotic proteins.

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Acknowledgements

Work by the authors was supported by grants from the New South Wales State Cancer Council and the Melanoma and Skin Cancer Institute, Sydney, Australia.

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Correspondence to Peter Hersey.

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DATABASES

CancerNet:

melanoma

 LocusLink:

APAF1

ARF

BAX

BCL2

BCL-XL

BFL-1

BID

CAD

caspase-3

caspase-6

caspase-7

caspase-8

caspase-9

cytochrome c

ERK1

ERK2

FADD

FASL

FLASH

FLICE

FLIP

granzyme B

IAP1

IAP2

ICAD

IFN-α2

IFN-γ

IKK

IL-2

IL-6

IL-15

JAK

lamin

MAGE

MCL1

MDM2

ML-IAP

NF-κB

p38 MAPK

p53

PARP

perforin

phosphatidylinositol 3-kinase

RAS

RIP

SMAC

STAT

survivin

TNF-α

TRADD

TRAF2

TRAIL

TRAIL-R1

TRAIL-R2

TRAIL-R3

TRAIL-R4

TWEAK

XIAP

 Medscape DrugInfo:

cisplatin

doxorubicin

DTIC

temozolomide

vinblastine

Glossary

APOPTOSOME

A caspase-activating complex that is formed when cytochrome c is released from mitochondria. It initiates oligomerization of APAF1, which binds procaspase-9 and thereby initiates the caspase cascade that leads to programmed cell death.

LYMPHOID INFILTRATES

The appearance of lymphocytes infiltrating into tissues that are not normally associated with traffic of lymphocytes.

CYTOTOXIC T LYMPHOCYTES

(CTLs). Lymphocytes that have the ability to kill other cells. They usually express CD8.

ANTIBODY-DEPENDENT COMPLEMENT LYSIS

Antibodies can kill target cells by binding complement, which forms pores in the cell membrane and leads to phagocytosis or lysis.

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY

Cells interact with the Fc region of antibodies on a target cell through Fc receptors on their surface to mediate cell killing.

NATURAL KILLER CELLS

Lymphocytes that express receptors for the Fc region of antibody and can therefore kill cells to which antibody is bound. They are referred to as natural killers because they do not need to be activated by antigen to carry out their cytotoxic role.

GRANZYME B

Granzymes are enzymes located in granules in cytotoxic lymphocytes. Granzyme B has been implicated in cell death and, like caspases, cleaves its substrates at the carboxyl side of aspartate residues.

DEATH DOMAINS

Regions of 80 amino acids in the cytoplasmic component of tumour necrosis factor receptor family members that bind to similar regions on adaptor proteins.

ADAPTOR PROTEINS

These bind to caspases-8 and -10 through death effector domains (DEDs).

PRODOMAINS

Prodomains are regions of caspases that are cleaved at aspartate residues to form the active caspase. The initiator caspases have long prodomains and bind to adaptor proteins. The active caspases are usually tetramers of two long and two short components.

DEATH-INDUCING SIGNALLING COMPLEX

(DISC). A complex containing tumour necrosis factor receptors, adaptor proteins and caspase-8. It is functionally analogous to the apoptosome in that it initiates the caspase cascade, leading to programmed cell death.

SURROGATE ENDPOINT

A preclinical marker that correlates with the true endpoint in a clinical trial.

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Hersey, P., Zhang, X. How melanoma cells evade trail-induced apoptosis. Nat Rev Cancer 1, 142–150 (2001). https://doi.org/10.1038/35101078

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