Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation

Rakefet Ben-Yishay, Opher Globus, Nora Balint-Lahat, Sheli Arbili-Yarhi, Neta Bar-Hai, Vered Bar, Sara Aharon, Anna Kosenko, Adi Zundelevich, Raanan Berger, Dana Ishay-Ronen

Research output: Contribution to journalArticlepeer-review

Abstract

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.

Original languageEnglish
Article number1506
JournalCells
Volume13
Issue number17
DOIs
StatePublished - 9 Sep 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • adipogenesis
  • breast cancer
  • differentiation therapy
  • EMT
  • MEK inhibitor
  • PPARγ agonist
  • thiazolidinediones

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