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.

• Authors: Eric Ciamporcero, Martina Daga, Stefania Pizzimenti, Antonella Roetto, Chiara Dianzani, Alessandra Compagnone, Antonietta Palmieri, Chiara Ullio, Luigi Cangemi, Roberto Pili, Giuseppina Barrera
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 115 Pg. 447-457 (02 01 2018) ISSN: 1873-4596 [Electronic] United States
• PMID: 29248722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Antioxidants
• FOXM1 protein, human
• Forkhead Box Protein M1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Phosphoproteins
• RNA, Small Interfering
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Cisplatin

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Antioxidants (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Forkhead Box Protein M1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidation-Reduction
• Oxidative Stress
• Phosphoproteins (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptor Cross-Talk
• Transcription Factors
• Urinary Bladder Neoplasms (drug therapy, genetics)
• YAP-Signaling Proteins