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A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Vaishnavi Muralikrishnan1, Fang Fang2, Tyler C Given1

  • 1Cell, Molecular and Cancer Biology Graduate Program, Medical Sciences Department, Indiana University School of Medicine, Bloomington, IN 47405, USA.

Cancers
|July 27, 2022
PubMed

Insights

Aldehyde dehydrogenase 1A1 (ALDH1A1) is crucial for ovarian cancer stem cell (OCSC) survival. Inhibiting ALDH1A1 with compound 974 reduces chemoresistance and recurrence, offering a potential clinical strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ovarian cancer is often detected late, leading to recurrence and chemoresistance.
  • Ovarian cancer stem cells (OCSCs) are implicated in the development of chemoresistant tumors.
  • Residual OCSCs survive chemotherapy, contributing to disease relapse.

Purpose of the Study:

  • To investigate the role of aldehyde dehydrogenase 1A1 (ALDH1A1) in OCSC survival.
  • To identify and characterize a novel ALDH1A1 inhibitor, compound 974.
  • To elucidate the mechanism by which ALDH1A1 regulates stemness in OCSCs.

Main Methods:

  • Treatment of OCSCs with compound 974.
  • Assays for ALDH activity, stemness gene expression, and spheroid/colony formation.
  • In vivo limiting dilution assay to assess CSC frequency.
  • Transcriptomic sequencing to analyze gene expression changes.
  • Functional assays to confirm inhibition of chemotherapy-induced senescence and stemness.

Main Results:

  • Compound 974 significantly inhibited ALDH activity, stemness gene expression, and OCSC formation in vitro.
  • In vivo studies showed that 974 significantly reduced the frequency of cancer stem cells (CSCs).
  • Transcriptomic analysis revealed downregulation of stemness, chemoresistance, and senescence-associated secretory phenotype (SASP) genes.
  • Compound 974 inhibited platinum-based chemotherapy-induced senescence and stemness.

Conclusions:

  • ALDH1A1 is essential for the survival and stemness of ovarian cancer stem cells.
  • Inhibition of ALDH1A1 by compound 974 suppresses OCSC stemness and chemotherapy-induced senescence.
  • Targeting ALDH1A1 with small-molecule inhibitors in combination with chemotherapy is a promising strategy to prevent ovarian cancer recurrence with clinical potential.
Keywords:
ALDH1A1cancer stem cellschemotherapy resistanceovarian cancersenescence

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