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Cardamonin inhibits cell proliferation by caspase-mediated cleavage of Raptor

Yanting Zhu1, Jintuo Zhou1, Peiguang Niu1

  • 1Department of Pharmacy, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou, 350001, Fujian, China.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|October 12, 2020
PubMed

Insights

Cardamonin inhibits cancer cell growth by triggering caspase-mediated degradation of Raptor, a key component of mTORC1 signaling. This mechanism reduces mTORC1 activity, leading to decreased cell viability and increased apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) pathway is crucial for cell growth and proliferation, and its dysregulation is implicated in various cancers.
  • Cardamonin, a natural compound, exhibits antiproliferative effects, but its precise molecular targets and mechanisms remain incompletely understood.
  • Raptor is a critical regulatory protein within the mTORC1 complex, and its modulation is a potential therapeutic strategy.

Purpose of the Study:

  • To elucidate the mechanism by which cardamonin exerts its antiproliferative effects, specifically focusing on its impact on Raptor expression and mTORC1 activity.
  • To investigate the role of caspases in cardamonin-induced Raptor degradation.
  • To analyze caspase expression patterns in serous cystadenocarcinoma and normal tissues.

Main Methods:

  • Gene expression analysis of caspases using TCGA and GTEx data.
  • Caspase activity monitoring via colorimetric assay kits.
  • Western blotting to detect mTORC1 and apoptosis-associated proteins.
  • Methyl thiazolyl tetrazolium (MTT) assay for cell viability assessment.
  • Treatment with cardamonin, cisplatin, and caspase inhibitor z-VAD-fmk in SKOV3 and HeLa cells.

Main Results:

  • Differential expression of caspases (excluding caspase-1) was observed between serous cystadenocarcinoma and normal tissues.
  • Cardamonin activated caspase-6 and caspase-8, leading to the cleavage of Raptor in SKOV3 cells.
  • Cardamonin treatment resulted in decreased mTORC1 activity, reduced cell viability, and induced apoptosis, effects rescued by z-VAD-fmk.
  • Similar effects were observed in HeLa cells, but only at high cardamonin concentrations.

Conclusions:

  • Cardamonin-induced antiproliferative effects are mediated, at least in part, through the caspase-dependent cleavage and degradation of Raptor.
  • This cleavage leads to the downregulation of mTORC1 activity, ultimately inhibiting cell viability and promoting apoptosis.
  • Caspase-mediated Raptor degradation represents a significant mechanism by which cardamonin regulates mTORC1 signaling and exhibits anti-cancer properties.
Keywords:
CardamoninCaspaseRaptormTORC1

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