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FEBS Lett. 2015 Dec 21;589(24 Pt B):4097-105. doi: 10.1016/j.febslet.2015.11.009. Epub 2015 Nov 25.

Targeting cholesterol with β-cyclodextrin sensitizes cancer cells for apoptosis.

Author information

1
Kansai Medical University, Department of Anesthesiology, Hirakata 573-1010, Japan. Electronic address: rudy.yamaguchi@hushmail.com.
2
National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA 92093, USA.
3
Kansai Medical University, Department of Anesthesiology, Hirakata 573-1010, Japan.

Abstract

We found that targeting cholesterol with beta-cyclodextrin (bCD) and its derivatives disrupted signal transduction between PI3K and AKT, attenuating AKT pro-survival signals. In their absence, 2-deoxyglucose (2DG) caused anti-apoptotic protein Mcll to dissociate from pro-apoptotic Bak at mitochondria. Normally Bak is sequestered by its inhibitory associations with Mcll and Bcl-xL, and only when Bak is released from both, is it free to form oligomers through which cytochrome c can escape into the cytosol. Thus an addition of a bcl-2 antagonist dissociates Bak from Bcl-xL, triggering cytochrome c release and inducing apoptosis. 2DG-bCD can also sensitize type II cancer cells for TRAIL-mediated apoptosis.

KEYWORDS:

2-Deoxyglucose; ABT-263; AKT; Apoptosis; Bcl2; Beta-cyclodextrin; Cancer; Cancer therapy; Epidermal growth factor; Insulin-like growth factor 1; Mcl1; Mitochondria; Pancreatic cancer; Phosphoinositide 3-kinase; Pro-survival signal; Receptor tyrosine kinase; TNF-related apoptosis-inducing ligand

PMID:
26606906
DOI:
10.1016/j.febslet.2015.11.009
[Indexed for MEDLINE]
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