Killing Breast Cancer Cells through Activation of the Apoptosome
Abstract
In response to a variety of different stressors, cells initiate a death program that is carried out by a family of cysteine proteases known as caspases. Caspase activation in response to chemotherapeutics typically proceeds through pathways that induce transit of cytochrome c from the intermembrane space of the mitochondria to the cytoplasm. Engagement of a cytosolic protein, Apaf-1, by cytochrome c nucleates the formation of a structure known as the apoptosome, in which caspase 9 is activated by Apaf-1/cytochrome c. For many tumor types (eg. ovarian, leukemias, prostate cancers), chemotherapy fails either because the agents employed fail to trigger the release of mitochondrial cytochrome c or because the apoptosome is in some way defective and so cannot respond to cytochrome c. However, in analyzing a large battery of breast cancer cell lines, we made the surprising discovery that they were exquisitely sensitive to cytochrome c, dying much more rapidly than normal breast cells in response to even low levels of cytoplasmic cytochrome c. Why then are breast cancers not rapidly and uniformly killed by chemotherapeutics? Our initial analysis indicates that breast cancer cells are highly variable in their ability to release cytochrome c following treatment with chemotherapeutic agents, despite their uniform susceptibility to cytochrome c once it has appeared in the cytoplasm. These findings suggest that treatments able to bypass the mitochondria and activate the apoptosome directly (ie. mimic mitochondrially-released cytochrome c) might be more effective than conventional therapeutics in inducing the death of breast cancer cells. This report documents our initial attempts to access this pathway therapeutically.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2007
- Accession Number
- ADA473389
Entities
People
- Sally Kornbluth
Organizations
- Duke University