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Molecular mechanisms associated with chemoresistance in esophageal cancer

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Abstract

Esophageal cancer (EC) is one of the most incident and lethal tumors worldwide. Although surgical resection is an important approach in EC treatment, late diagnosis, metastasis and recurrence after surgery have led to the management of adjuvant and neoadjuvant therapies over the past few decades. In this scenario, 5-fluorouracil (5-FU) and cisplatin (CISP), and more recently paclitaxel (PTX) and carboplatin (CBP), have been traditionally used in EC treatment. However, chemoresistance to these agents along EC therapeutic management represents the main obstacle to successfully treat this malignancy. In this sense, despite the fact that most of chemotherapy drugs were discovered several decades ago, in many cases, including EC, they still represent the most affordable and widely employed treatment approach for these tumors. Therefore, this review summarizes the main mechanisms through which the response to the most widely chemotherapeutic agents used in EC treatment is impaired, such as drug metabolism, apoptosis resistance, cancer stem cells (CSCs), cell cycle, autophagy, energetic metabolism deregulation, tumor microenvironment and epigenetic modifications.

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Abbreviations

3’-UTR:

3’-Untranslated region

5’-UTR:

5’-Untranslated region

5-FU:

5-Fluorouracil

ABCB:

ATP binding cassette subfamily B

ADAM:

Disintegrin and metalloproteinase domain-containing protein

AKT:

Protein kinase B

AMP:

Adenosine monophosphate

AMPK:

AMP-activated protein kinase

APC/C:

Anaphase-promoting complex/cyclosome

ARF:

ADP-ribosylation factor

BMI1:

B lymphoma Mo-MLV insertion region 1 homolog

BubR:

Budding uninhibited by benzimidazole-related

CAFs:

Cancer-associated fibroblasts

CBDCA:

Cyclobutane-1,1-dicarboxylate

CBP:

Carboplatin

CDH:

E-cadherin

CDHP:

5-Chloro-2,4-dihydroxypyridine

CDKN:

Cyclin-dependent kinase inhibitor

CISP:

Cisplatin

COX:

Cyclooxygenase

CROSS:

Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study

CSC:

Cancer stem cell

CtBP:

C-terminal binding protein

CTR:

Copper uptake protein

CXCR:

C–X–C chemokine receptor

DHFU:

Dihydrofluorouracil

DKK:

Dickkopf-related protein

DNMT:

DNA methyltransferases

DPD:

Dihydropyrimidine dehydrogenase

dUMP:

Deoxyuridine monophosphate

dUTP:

Deoxyuridine triphosphate

dUTPase:

Deoxyuridine triphosphatase

E2F:

E2F transcription factor

EAC:

Esophageal adenocarcinoma

EC:

Esophageal cancer

ECRG:

EC related gene

EGFR:

Epidermal growth factor receptor

eIF:

Eukaryotic translation initiation factor

ERCC:

Excision repair cross-complementing

ERK:

Extracellular signal-regulated kinase

ESCC:

Esophageal squamous cell carcinoma

EZH:

Enhancer of zeste homolog

FBXO:

F-box only protein

FDA:

Food and Drug Administration

FdUDP:

Fluorodeoxyuridine diphosphate

FdUMP:

Fluorodeoxyuridine monophosphate

FdUTP:

Fluorodeoxyuridine triphosphate

FOX:

Forkhead box

FpD:

Fluoropyrimidines

FUDP:

Fluorouridine diphosphate

FUDR:

Fluorodeoxyuridine

FUMP:

Fluorouridine monophosphate

FUR:

Fluorouridine

FUTP:

Fluorouridine triphosphate

GSH:

Glutathione

GST:

Glutathione-S-transferase

HIF:

Hypoxia-inducible factor

HMGN:

High mobility group nucleosome binding domain

IC50 :

The half maximal inhibitory concentration

ID:

Inhibitor of DNA binding

IGF:

Insulin-like growth factor

IL:

Interleukin

LC:

MTb-associated protein light chain

LEF:

Lymphoid enhancer binding factor

linc-ROR:

Long intergenic non-protein coding RNA regulator of reprogramming

lncRNA:

Long non-coding RNA

MAPK:

Mitogen-activated protein kinase

MDR:

Multidrug resistant transporter

Mel:

Melanoma nuclear protein

miR:

MicroRNA

MMR:

Mismatch repair

MT:

Metallothionein

MTb:

Microtubules

N-BFIS:

N-benzoylphenylisoserine

NCCN:

National Comprehensive Cancer Network

NER:

Nucleotide excision repair

NF-κB:

Nuclear factor-κB

OPRT:

Orotate phosphoribosyltransferase

p70S6K:

Ribosomal protein S6 kinase

PAI:

Plasminogen activator inhibitor

PAK:

P21-activated kinase

PCNA:

Proliferating cell nuclear antigen

PD:

Programmed cell death protein

PDCD:

Programmed cell death protein

PD-L:

Programmed death-ligand

PI3K:

Phosphatidylinositol 3-kinase

Pink:

PTEN-induced kinase

PLK:

Polo-like kinase

PPAR:

Peroxisome proliferator-activated receptor

PPi :

Pyrophosphate

PRMT:

Protein arginine N-methyltransferase

PRPP:

Phosphoribosyl pyrophosphate

Pt-Ch:

Platinum-chemotherapeutic drugs

PTX:

Paclitaxel

RAC:

Ras-related C3 botulinum toxin substrate

RACK:

Receptor of activated protein C kinase

RR:

Ribonucleotide reductase

SAC:

Spindle assembly checkpoint

SCNAs:

Somatic copy-number alterations

SNP:

Single nucleotide polymorphism

SOX:

SRY-Box transcription factor

STAT:

Signal transducer and activator of transcription

TCGA:

The Cancer Genome Atlas

TGF:

Transforming growth factor

TIGAR:

TP53-induced glycolysis and apoptosis regulator

TK:

Thymidine kinase

TP:

Thymidine phosphorylase

TR:

Tandem repeat

TS:

Thymidylate synthase

TXN:

Taxanes

UK:

Uridine kinase

UP:

Uridine phosphorylase

VEGFR:

Vascular endothelial growth factor receptor

VRK:

Vaccinia-related kinase

XPF:

Xeroderma pigmentosum group F complementing factor

YAP:

Yes-associated protein

γ-H2AX:

H2AX histone phosphorylated on Ser-139

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Funding

We would like to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq–Brazil), Fundação de Amparo à Pesquisa Carlos Chagas Filho (FAPERJ-Brazil), Swiss Bridge Foundation and Programa de Oncobiologia/Fundação André Frauzino de Pesquisas para o Câncer.

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  1. Matheus Lohan-Codeço and Maria Luísa Barambo-Wagner equally contributed to the work.

Authors and Affiliations

  1. Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Programa de Pesquisa em Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Prédio do Centro de Ciências da Saúde–Cidade Universitária, Ilha do Fundão, Rua César Pernetta, 1766 (LS.3.01), Rio de Janeiro, RJ, Brasil

    Matheus Lohan-Codeço, Luiz Eurico Nasciutti & Antonio Palumbo Jr

  2. Programa de Carcinogênese Molecular Coordenação de Pesquisa, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37–6ºandar-Centro, Rio de Janeiro, RJ, 20231-050, Brazil

    Maria Luísa Barambo-Wagner, Luis Felipe Ribeiro Pinto & Nathalia Meireles Da Costa

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Lohan-Codeço, M., Barambo-Wagner, M.L., Nasciutti, L.E. et al. Molecular mechanisms associated with chemoresistance in esophageal cancer. Cell. Mol. Life Sci. 79, 116 (2022). https://doi.org/10.1007/s00018-022-04131-6

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