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Updated: Dec 26, 2025

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Decoding molecular interplay between RUNX1 and FOXO3a underlying the pulsatile IGF1R expression during acquirement of

Ajit C Dhadve1, Kishore Hari2, Bharat Rekhi3

  • 1Imaging Cell Signaling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|March 7, 2020
PubMed

Insights

Runt-related transcription factor 1 (RUNX1) and Forkhead Box O3 (FOXO3a) regulate Insulin-like growth factor 1 receptor (IGF1R) expression during ovarian cancer chemoresistance. RUNX1 inhibition reduces tumor growth and enhances drug sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Hyperactive Insulin-like Growth Factor-1 Receptor (IGF1R) signaling is linked to cancer therapy resistance.
  • Epithelial Ovarian Cancer (EOC) cells exhibit pulsatile IGF1R expression during platinum-taxol resistance acquisition.
  • Therapy can induce IGF1R upregulation in high-grade serous EOC patient tumors.

Purpose of the Study:

  • To identify novel transcriptional regulators of IGF1R during chemoresistance development in EOC.
  • To elucidate the cooperative and dynamic roles of RUNX1 and FOXO3a in modulating IGF1R expression.
  • To investigate the therapeutic potential of targeting the RUNX1-IGF1R axis in chemoresistant EOC.

Main Methods:

  • Investigated the roles of RUNX1 and FOXO3a in regulating IGF1R expression in EOC cells.
  • Analyzed the cooperative binding of RUNX1-FOXO3a to the IGF1R promoter.
  • Examined the influence of a Protein Kinase B (AKT)-FOXO3a negative feedback loop on IGF1R and FOXO3a expression.
  • Utilized in vivo molecular imaging to assess the effects of RUNX1 inhibition on tumor growth and drug sensitivity.

Main Results:

  • RUNX1 and FOXO3a cooperatively bind to the IGF1R promoter, driving an initial surge in IGF1R expression during resistance development.
  • This cooperation diminishes in highly resistant cells, leading to decreased IGF1R expression.
  • A negative feedback loop involving AKT and FOXO3a in resistant cells causes pulsatile IGF1R and FOXO3a expression.
  • RUNX1 inhibition in early resistant cells significantly reduced IGF1R promoter activity, tumorigenicity, and enhanced drug sensitivity.

Conclusions:

  • RUNX1 acts as a novel transcriptional regulator of IGF1R in EOC chemoresistance.
  • A dynamic interplay between RUNX1, FOXO3a, and AKT governs pulsatile IGF1R expression.
  • Targeting the RUNX1-IGF1R axis presents a promising therapeutic strategy for overcoming chemoresistance in EOC.
Keywords:
ChemoresistanceFOXO3aIGF1R regulationOvarian CancerRUNX1

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