Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer

Eric Ciamporcero, Martina Daga, Stefania Pizzimenti, Antonella Roetto, Chiara Dianzani, Alessandra Compagnone, Antonietta Palmieri, Chiara Ullio, Luigi Cangemi, Roberto Pili, Giuseppina Barrera

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Redox adaptation plays an important role in cancer cells drug resistance. The antioxidant response is principally mediated by the transcription factor Nrf2, that induces the transcriptional activation of several genes involved in GSH synthesis, chemoresistance, and cytoprotection. YAP is emerging as a key mediator of chemoresistance in a variety of cancers, but its role in controlling the antioxidant status of the cells is yet elusive. Here, we show that impairing YAP protein expression reduced GSH content and Nrf2 protein and mRNA expression in bladder cancer cells. Moreover, in YAP knocked down cells the expression of FOXM1, a transcription factor involved in Nrf2 transcription, was down-regulated and the silencing of FOXM1 reduced Nrf2 expression. On the other hand, the silencing of Nrf2, as well as the depletion of GSH by BSO treatment, inhibited YAP expression, suggesting that cross-talk exists between YAP and Nrf2 proteins. Importantly, we found that silencing either YAP or Nrf2 enhanced sensitivity of bladder cancer cells to cytotoxic agents and reduced their migration. Furthermore, the inhibition of both YAP and Nrf2 expressions significantly increased cytotoxic drug sensitivity and synergistically reduced the migration of chemoresistant bladder cancer cells. These findings provide a rationale for targeting these transcriptional regulators in patients with chemoresistant bladder cancer, expressing high YAP and bearing a proficient antioxidant system.

Original languageEnglish (US)
Pages (from-to)447-457
Number of pages11
JournalFree Radical Biology and Medicine
Volume115
DOIs
StatePublished - Feb 1 2018

Fingerprint

Crosstalk
Urinary Bladder Neoplasms
Antioxidants
Cells
Transcription Factors
Bearings (structural)
Proteins
Cytotoxins
Transcription
Pharmaceutical Preparations
Cytoprotection
Genes
Chemical activation
Drug Resistance
Messenger RNA
Transcriptional Activation
Oxidation-Reduction
Neoplasms

Keywords

  • Bladder cancer cells
  • Chemoresistance
  • FOXM1
  • Glutathione
  • Nrf2
  • YAP

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer. / Ciamporcero, Eric; Daga, Martina; Pizzimenti, Stefania; Roetto, Antonella; Dianzani, Chiara; Compagnone, Alessandra; Palmieri, Antonietta; Ullio, Chiara; Cangemi, Luigi; Pili, Roberto; Barrera, Giuseppina.

In: Free Radical Biology and Medicine, Vol. 115, 01.02.2018, p. 447-457.

Research output: Contribution to journalArticle

Ciamporcero, E, Daga, M, Pizzimenti, S, Roetto, A, Dianzani, C, Compagnone, A, Palmieri, A, Ullio, C, Cangemi, L, Pili, R & Barrera, G 2018, 'Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer', Free Radical Biology and Medicine, vol. 115, pp. 447-457. https://doi.org/10.1016/j.freeradbiomed.2017.12.005
Ciamporcero, Eric ; Daga, Martina ; Pizzimenti, Stefania ; Roetto, Antonella ; Dianzani, Chiara ; Compagnone, Alessandra ; Palmieri, Antonietta ; Ullio, Chiara ; Cangemi, Luigi ; Pili, Roberto ; Barrera, Giuseppina. / Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer. In: Free Radical Biology and Medicine. 2018 ; Vol. 115. pp. 447-457.
@article{a802ddbbae1a4caa956f42e082a3f4a7,
title = "Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer",
abstract = "Redox adaptation plays an important role in cancer cells drug resistance. The antioxidant response is principally mediated by the transcription factor Nrf2, that induces the transcriptional activation of several genes involved in GSH synthesis, chemoresistance, and cytoprotection. YAP is emerging as a key mediator of chemoresistance in a variety of cancers, but its role in controlling the antioxidant status of the cells is yet elusive. Here, we show that impairing YAP protein expression reduced GSH content and Nrf2 protein and mRNA expression in bladder cancer cells. Moreover, in YAP knocked down cells the expression of FOXM1, a transcription factor involved in Nrf2 transcription, was down-regulated and the silencing of FOXM1 reduced Nrf2 expression. On the other hand, the silencing of Nrf2, as well as the depletion of GSH by BSO treatment, inhibited YAP expression, suggesting that cross-talk exists between YAP and Nrf2 proteins. Importantly, we found that silencing either YAP or Nrf2 enhanced sensitivity of bladder cancer cells to cytotoxic agents and reduced their migration. Furthermore, the inhibition of both YAP and Nrf2 expressions significantly increased cytotoxic drug sensitivity and synergistically reduced the migration of chemoresistant bladder cancer cells. These findings provide a rationale for targeting these transcriptional regulators in patients with chemoresistant bladder cancer, expressing high YAP and bearing a proficient antioxidant system.",
keywords = "Bladder cancer cells, Chemoresistance, FOXM1, Glutathione, Nrf2, YAP",
author = "Eric Ciamporcero and Martina Daga and Stefania Pizzimenti and Antonella Roetto and Chiara Dianzani and Alessandra Compagnone and Antonietta Palmieri and Chiara Ullio and Luigi Cangemi and Roberto Pili and Giuseppina Barrera",
year = "2018",
month = "2",
day = "1",
doi = "10.1016/j.freeradbiomed.2017.12.005",
language = "English (US)",
volume = "115",
pages = "447--457",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer

AU - Ciamporcero, Eric

AU - Daga, Martina

AU - Pizzimenti, Stefania

AU - Roetto, Antonella

AU - Dianzani, Chiara

AU - Compagnone, Alessandra

AU - Palmieri, Antonietta

AU - Ullio, Chiara

AU - Cangemi, Luigi

AU - Pili, Roberto

AU - Barrera, Giuseppina

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Redox adaptation plays an important role in cancer cells drug resistance. The antioxidant response is principally mediated by the transcription factor Nrf2, that induces the transcriptional activation of several genes involved in GSH synthesis, chemoresistance, and cytoprotection. YAP is emerging as a key mediator of chemoresistance in a variety of cancers, but its role in controlling the antioxidant status of the cells is yet elusive. Here, we show that impairing YAP protein expression reduced GSH content and Nrf2 protein and mRNA expression in bladder cancer cells. Moreover, in YAP knocked down cells the expression of FOXM1, a transcription factor involved in Nrf2 transcription, was down-regulated and the silencing of FOXM1 reduced Nrf2 expression. On the other hand, the silencing of Nrf2, as well as the depletion of GSH by BSO treatment, inhibited YAP expression, suggesting that cross-talk exists between YAP and Nrf2 proteins. Importantly, we found that silencing either YAP or Nrf2 enhanced sensitivity of bladder cancer cells to cytotoxic agents and reduced their migration. Furthermore, the inhibition of both YAP and Nrf2 expressions significantly increased cytotoxic drug sensitivity and synergistically reduced the migration of chemoresistant bladder cancer cells. These findings provide a rationale for targeting these transcriptional regulators in patients with chemoresistant bladder cancer, expressing high YAP and bearing a proficient antioxidant system.

AB - Redox adaptation plays an important role in cancer cells drug resistance. The antioxidant response is principally mediated by the transcription factor Nrf2, that induces the transcriptional activation of several genes involved in GSH synthesis, chemoresistance, and cytoprotection. YAP is emerging as a key mediator of chemoresistance in a variety of cancers, but its role in controlling the antioxidant status of the cells is yet elusive. Here, we show that impairing YAP protein expression reduced GSH content and Nrf2 protein and mRNA expression in bladder cancer cells. Moreover, in YAP knocked down cells the expression of FOXM1, a transcription factor involved in Nrf2 transcription, was down-regulated and the silencing of FOXM1 reduced Nrf2 expression. On the other hand, the silencing of Nrf2, as well as the depletion of GSH by BSO treatment, inhibited YAP expression, suggesting that cross-talk exists between YAP and Nrf2 proteins. Importantly, we found that silencing either YAP or Nrf2 enhanced sensitivity of bladder cancer cells to cytotoxic agents and reduced their migration. Furthermore, the inhibition of both YAP and Nrf2 expressions significantly increased cytotoxic drug sensitivity and synergistically reduced the migration of chemoresistant bladder cancer cells. These findings provide a rationale for targeting these transcriptional regulators in patients with chemoresistant bladder cancer, expressing high YAP and bearing a proficient antioxidant system.

KW - Bladder cancer cells

KW - Chemoresistance

KW - FOXM1

KW - Glutathione

KW - Nrf2

KW - YAP

UR - http://www.scopus.com/inward/record.url?scp=85039729079&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039729079&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2017.12.005

DO - 10.1016/j.freeradbiomed.2017.12.005

M3 - Article

C2 - 29248722

AN - SCOPUS:85039729079

VL - 115

SP - 447

EP - 457

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -