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Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells

Rakesh Kumar Sharma1, Rohit Sahai2, Nishakumari Chentunarayan Singh2

  • 1Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.

Biochemical and Biophysical Research Communications
|March 28, 2025
PubMed

Insights

Ormeloxifene (ORM) induces colon cancer cell death by promoting mitochondrial fission and autophagy. Inhibiting autophagy or mitochondrial fission reduces ORM

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Ormeloxifene (ORM), a selective estrogen receptor modulator (SERM), is an oral contraceptive with demonstrated anti-cancer properties, particularly in breast cancer.
  • Its potential anti-cancer effects in colon cancer warrant further investigation.

Purpose of the Study:

  • To investigate the anti-cancer effects of Ormeloxifene (ORM) on colon cancer cells.
  • To elucidate the underlying mechanisms, focusing on mitochondrial dynamics and autophagy-associated cell death.

Main Methods:

  • Utilized immunofluorescence staining, confocal microscopy, and transmission electron microscopy (TEM) to assess autophagy markers (LC3II, Beclin1, Atg7) and autophagosome formation.
  • Confirmed autophagic flux using Bafilomycin A1 co-treatment and tandem mRFP-GFP-LC3 (tfLC3) transfection.
  • Analyzed mitochondrial dynamics, including reactive oxygen species (ROS) generation, mitochondrial fission/fusion protein levels, and ultrastructural changes via TEM.
  • Investigated the role of mitochondrial fission by inhibiting it and observing effects on cell survival and autophagy.

Main Results:

  • ORM treatment significantly elevated autophagy markers and induced autophagosome/autophagolysosome formation in colon cancer cells.
  • ORM triggered mitochondrial reactive oxygen species (ROS) generation, increased mitochondrial fission, and decreased mitochondrial fusion.
  • Inhibition of autophagy reduced ORM-induced apoptosis, indicating pro-death autophagy.
  • Blocking mitochondrial fission enhanced cell survival and decreased autophagic markers, suggesting ORM-induced autophagy is dependent on mitochondrial fission.

Conclusions:

  • Ormeloxifene (ORM) exhibits anti-cancer activity in colon cancer cells through a novel mechanism involving mitochondrial dynamics.
  • ORM promotes autophagy-associated cell death, which is critically dependent on mitochondrial fission.
  • Targeting mitochondrial dynamics represents a potential therapeutic strategy for colon cancer using ORM.
Keywords:
AutophagyCancerCell deathMitochondrial fissionOrmeloxifene

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