The relationship between platinum drug resistance and epithelial–mesenchymal transition

Abstract

One of the most commonly used chemotherapeutics, platinum drugs are used to treat a wide range of cancer types. Although many cancers initially respond well to those drugs, drug resistance occurs frequently and different molecular mechanisms have been associated with it. However, predictive biomarkers of cellular response in specific tumour types still do not exist. Epithelial–mesenchymal transition (EMT) is a malignant cancer phenotype characterized by aggressive invasion and metastasis, and resistance to apoptosis. Recent studies indicate that EMT accompanies the development of drug resistance to a number of cancer chemotherapies. The link between these two phenomena is still not elucidated, although several important molecules involved in both these complex processes, such as transcription factors (SNAIL, TWIST, ZEB, etc.) and miRNAs (miRNA-200 family, miR-15, miR-186, etc.) have been recognized as important. This article reviews numerous unresolved issues regarding platinum drugs resistance and EMT, the complexity of the signalling networks that regulate those two phenomena and their importance in tumour response and spreading which are becoming focuses of interest of many scientists. This article also presents molecules involved in platinum resistance and EMT as possible targets for new cancer therapy.

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Abbreviations

AKT:

Protein kinase B

ATP7A and ATP7B:

Copper-transporting P-type ATPase 7A and 7B

BAK:

BCL-2 homologous antagonist/killer

BAX:

BCL-2-like protein 4

BCL-2:

B-cell lymphoma 2

BMP:

Bone morphogenetic protein

cMOAT:

Canalicular multispecific organic anion transporter 1

CTR1:

Copper transporter

DYRK2:

Dual specificity tyrosine phosphorylation regulated kinase 2

EGF:

Epidermal growth factor

EMT:

Epithelial–mesenchymal transition

FAS:

Death receptor

FGF:

Fibroblast growth factors

FOX:

Forkhead box

GSH:

Glutathione

HGF:

Hepatocyte growth factor

IAP:

Inhibitor of apoptosis

ILK:

Integrin-linked kinase

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinases

MDR1/P-gp:

Multidrug-resistant protein 1/P-glycoprotein

MET:

Mesenchymal–epithelial transition

MET proto-oncogene:

Receptor tyrosine kinase

miRNA:

Micro-RNA

miR:

Micro-RNA

MMP2:

Matrix metalloproteinase-2

MMP3:

Matrix metalloproteinase-3

MMP9:

Matrix metalloproteinase-9

NF-κB:

Nuclear factor κ-light-chain-enhancer of activated B cells

p21:

Cyclin-dependent kinase inhibitor 1

p53:

Tumour protein 53

p63:

Tumour protein 63

PEBP4:

Phosphatidylethanolamine binding protein 4

PI3-K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PKB:

Serine/threonine protein kinase B

PTEN:

Phosphatase and tensin homolog

RKIP:

Raf kinase inhibitor protein

RNAi:

RNA interference

ROS:

Reactive oxygen species

SMAD:

SMAD protein

Snail1 and 2:

Zinc finger protein Snail1 and 2

SOX:

SRY-related HMG-box

STAT3:

Signal-transducer-and-activator-of-transcription 3

TGFβ:

Transforming growth factor β

TWIST1 and 2:

TWIST-related protein 1 and 2

ZEB1 and 2:

Zinc finger E-box-binding homeobox 1 and 2

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Acknowledgements

The author would like to thank Senior Scientist Maja Osmak Ph.D., Assistant Professor Maja T. Tomicic Ph.D. and George E. Duran B.Sc. for critical reading of the manuscript.

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Correspondence to Anamaria Brozovic.

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Brozovic, A. The relationship between platinum drug resistance and epithelial–mesenchymal transition. Arch Toxicol 91, 605–619 (2017). https://doi.org/10.1007/s00204-016-1912-7

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Keywords

  • Epithelial–mesenchymal transition
  • Cisplatin
  • Platinum drugs
  • Drug resistance
  • Tumour