Snail-Induced Epithelial-to-Mesenchymal Transition Enhances P-gp-Mediated Multidrug Resistance in HCC827 Cells

The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.

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Resistance to paclitaxel induces glycophenotype changes and mesenchymal-to-epithelial transition activation in the human prostate cancer cell line PC-3

Tumor Biology ◽

10.1177/1010428320957506 ◽

2020 ◽

Vol 42 (9) ◽

pp. 101042832095750

Author(s):

Leonardo Marques da Fonseca ◽

Danilo Macedo Calvalhan ◽

Jose Osvaldo Previato ◽

Lucia Mendonça Previato ◽

Leonardo Freire-de-Lima

Keyword(s):

Multidrug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Continuous Treatment ◽

Human Prostate ◽

Cross Resistance ◽

Mesenchymal Transition ◽

Resistance Phenotype ◽

Chemical Structures

The development of the multidrug resistance phenotype is one of the major challenges faced in the treatment of cancer. The multidrug resistance phenotype is characterized by cross-resistance to drugs with different chemical structures and mechanisms of action. In this work, we hypothesized that the acquisition of resistance in cancer is accompanied by activation of the epithelial-to-mesenchymal transition process, where the tumor cell acquires a more mobile and invasive phenotype; a fundamental step in tumor progression and in promoting the invasion of other organs and tissues. In addition, it is known that atypical glycosylations are characteristic of tumor cells, being used as biomarkers. We believe that the acquisition of the multidrug resistance phenotype and the activation of epithelial-to-mesenchymal transition provoke alterations in the cell glycophenotype, which can be used as glycomarkers for chemoresistance and epithelial-to-mesenchymal transition processes. Herein, we induced the multidrug resistance phenotype in the PC-3 human prostate adenocarcinoma line through the continuous treatment with the drug paclitaxel. Our results showed that the induced cell multidrug resistance phenotype (1) acquired a mixed profile between epithelial and mesenchymal phenotypes and (2) modified the glycophenotype, showing an increase in the level of sialylation and in the number of branched glycans. Both mechanisms are described as indicators of poor prognosis.

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Glycosylation in Cancer: Interplay between Multidrug Resistance and Epithelial-to-Mesenchymal Transition?

Frontiers in Oncology ◽

10.3389/fonc.2016.00158 ◽

2016 ◽

Vol 6 ◽

Cited By ~ 16

Author(s):

Leonardo Marques da Fonseca ◽

Vanessa Amil da Silva ◽

Leonardo Freire-de-Lima ◽

José Osvaldo Previato ◽

Lucia Mendonça-Previato ◽

...

Keyword(s):

Multidrug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition

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The role of DUBs in the post-translational control of cell migration

Essays in Biochemistry ◽

10.1042/ebc20190022 ◽

2019 ◽

Vol 63 (5) ◽

pp. 579-594 ◽

Cited By ~ 2

Author(s):

Guillem Lambies ◽

Antonio García de Herreros ◽

Víctor M. Díaz

Keyword(s):

Cell Migration ◽

Translational Control ◽

Epithelial To Mesenchymal Transition ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Tgfβ Receptors ◽

Fundamental Process ◽

Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

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