The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells

BMC Cancer. 2024 May 14;24(1):587. doi: 10.1186/s12885-024-12316-4.

Abstract

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Keywords: Colon cancer; Hippo signaling; Oxaliplatin; TAZ; p53.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / genetics
  • Colonic Neoplasms* / metabolism
  • Colonic Neoplasms* / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • Hippo Signaling Pathway* / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin* / pharmacology
  • Porphyrins / pharmacology
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction* / drug effects
  • Trans-Activators* / genetics
  • Trans-Activators* / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins*
  • Tumor Protein p73 / genetics
  • Tumor Protein p73 / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Verteporfin / pharmacology
  • Verteporfin / therapeutic use
  • YAP-Signaling Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Organoplatinum Compounds
  • Oxaliplatin
  • Porphyrins
  • Protein Serine-Threonine Kinases
  • TP53 protein, human
  • TP73 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Verteporfin
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human