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 Blood, 15 May 2005, Vol. 105, No. 10, pp. 4070-4077.
Prepublished online as a Blood First Edition Paper on February 3, 2005; DOI 10.1182/blood-2004-10-4075.

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NEOPLASIA

Plasma membrane sequestration of apoptotic protease-activating factor-1 in human B-lymphoma cells: a novel mechanism of chemoresistance

Yu Sun, Sten Orrenius, Shazib Pervaiz, and Bengt Fadeel

From the Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; the Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and the Department of Physiology, National University of Singapore, Singapore.

Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm harboring chromosomal rearrangements of the c-myc oncogene. BL cells frequently resist apoptosis induction by chemotherapeutic agents; however, the mechanism of unresponsiveness has not been elucidated. Here, we show that cytochrome c fails to stimulate apoptosome formation and caspase activation in cytosolic extracts of human BL-derived cell lines, due to insufficient levels of apoptotic protease-activating factor-1 (Apaf-1). Enforced expression of Apaf-1 increased its concentration in the cytosolic compartment, restored cytochrome c-dependent caspase activation, and rendered the prototypic Raji BL cell line sensitive to etoposide- and staurosporine-induced apoptosis. Surprisingly, in nontransfected BL cells, the bulk of Apaf-1 was found to associate with discrete domains in the plasma membrane. Disruption of lipid raft domains or the actin cytoskeleton of Raji cells liberated Apaf-1 and restored sensitivity to cytochrome c–dependent apoptosis, indicating that constitutive Apaf-1 retained its ability to promote caspase activation. Moreover, disruption of lipid rafts sensitized BL cells to apoptosis induced by etoposide. Together, our findings suggest that ectopic (noncytosolic) localization of Apaf-1 may constitute a novel mechanism of chemoresistance in B lymphoma.


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