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Targeting cholesterol with β-cyclodextrin sensitizes cancer cells for apoptosis

Ryuji Yamaguchi1, Guy Perkins2, Kiichi Hirota1

  • 1Kansai Medical University, Department of Anesthesiology, Hirakata 573-1010, Japan.

FEBS Letters
|November 27, 2015
PubMed

Insights

Beta-cyclodextrin (bCD) disrupts PI3K/AKT signaling, enabling 2-deoxyglucose (2DG) to induce cancer cell apoptosis by releasing Bak. This combination sensitizes cells to TRAIL-mediated apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The PI3K/AKT pathway promotes cancer cell survival.
  • Cholesterol plays a role in cellular signaling.
  • Targeting apoptotic pathways is a key cancer treatment strategy.

Purpose of the Study:

  • To investigate the combined effects of cholesterol depletion and metabolic inhibition on cancer cell apoptosis.
  • To elucidate the molecular mechanisms underlying 2-deoxyglucose and beta-cyclodextrin-induced cell death.

Main Methods:

  • Utilizing beta-cyclodextrin (bCD) to target cellular cholesterol.
  • Employing 2-deoxyglucose (2DG) to inhibit glycolysis.
  • Analyzing protein-protein interactions (Mcl1-Bak, Bak-Bcl-xL) and cytochrome c release.
  • Assessing sensitization to TRAIL-mediated apoptosis in type II cancer cells.

Main Results:

  • bCD disrupted PI3K/AKT signaling, reducing pro-survival AKT activity.
  • In cholesterol-depleted cells, 2DG induced dissociation of Mcl1 from Bak at mitochondria.
  • This dissociation freed Bak to oligomerize, leading to cytochrome c release and apoptosis.
  • The 2DG-bCD combination sensitized type II cancer cells to TRAIL-induced apoptosis.

Conclusions:

  • Targeting cholesterol with bCD and inhibiting glycolysis with 2DG synergistically induce apoptosis in cancer cells.
  • The mechanism involves the disruption of AKT signaling and the subsequent release of Bak from inhibitory proteins.
  • This combined approach offers a potential strategy to enhance cancer therapy, particularly for TRAIL-resistant types.
Keywords:
2-DeoxyglucoseABT-263AKTApoptosisBcl2Beta-cyclodextrinCancerCancer therapyEpidermal growth factorInsulin-like growth factor 1Mcl1MitochondriaPancreatic cancerPhosphoinositide 3-kinasePro-survival signalReceptor tyrosine kinaseTNF-related apoptosis-inducing ligand

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