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Sulforaphane downregulated fatty acid synthase and inhibited microtubule-mediated mitophagy leading to apoptosis

Yuting Yan1,2,3, Yan Zhou1,2, Juntao Li1,2

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

Cell Death & Disease
|October 8, 2021
PubMed

Insights

Sulforaphane (SFN) triggers apoptosis in non-small cell lung cancer (NSCLC) by disrupting microtubule function and inhibiting mitophagy, leading to cancer cell death.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Sulforaphane (SFN) previously showed potential in inhibiting autophagy and inducing apoptosis in non-small cell lung cancer (NSCLC).
  • The precise subcellular mechanisms underlying SFN's anti-cancer effects remained largely unknown.

Purpose of the Study:

  • To elucidate the subcellular mechanisms by which SFN induces apoptosis in NSCLC cells.
  • To investigate the role of microtubules, fatty acid metabolism, and mitophagy in SFN's mechanism of action.

Main Methods:

  • High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze protein and metabolite changes.
  • Western blotting and co-immunoprecipitation to assess protein interactions and levels.
  • Transmission electron microscopy (TEM) for ultrastructural analysis of mitochondria.
  • Gene knockdown experiments (FASN, α-tubulin) to determine functional significance.

Main Results:

  • SFN depolymerized microtubules and downregulated fatty acid synthase (FASN), a key factor in cancer malignancy.
  • SFN inhibited fatty acid synthesis by downregulating FASN, ACACA, and ACLY, and decreased intracellular fatty acids and mitochondrial phospholipids.
  • SFN impaired mitophagy by inhibiting mitophagosome-lysosome fusion, leading to accumulation of abnormal mitochondria and inducing apoptosis, an effect linked to microtubule-NIX interactions.

Conclusions:

  • SFN induces apoptosis in NSCLC cells through a novel mechanism involving microtubule destabilization and inhibition of mitophagy.
  • The findings highlight the intricate interplay between microtubule dynamics, fatty acid metabolism, and mitophagy in SFN-mediated cancer cell death.
  • This study provides new subcellular insights into SFN's anti-cancer properties, potentially opening avenues for novel therapeutic strategies.

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