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 Blood, 15 May 2008, Vol. 111, No. 10, pp. 5152-5162.
Prepublished online as a Blood First Edition Paper on March 19, 2008; DOI 10.1182/blood-2007-10-116889.

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NEOPLASIA

BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide–induced cell death in myeloma

Alejo A. Morales1, Delia Gutman1, Kelvin P. Lee2, and Lawrence H. Boise1

1 Microbiology and Immunology and The Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, FL; and 2 Department of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY

The use of arsenic trioxide (ATO) to treat multiple myeloma (MM) is supported by preclinical studies as well as several phase 2 studies, but the precise mechanism(s) of action of ATO has not been completely elucidated. We used gene expression profiling to determine the regulation of apoptosis-related genes by ATO in 4 MM cell lines and then focused on Bcl-2 family genes. ATO induced up-regulation of 3 proapoptotic BH3-only proteins (Noxa, Bmf, and Puma) and down-regulation of 2 antiapoptotic proteins Mcl-1 and Bcl-XL. Coimmunoprecipitation demonstrated that Noxa and Puma bind Mcl-1 to release Bak and Bim within 6 hours of ATO addition. Bak and Bim are also released from Bcl-XL. Silencing of Bmf, Noxa, and Bim significantly protected cells from ATO-induced apoptosis, while Puma silencing had no effect. Consistent with a role for Noxa inhibition of Mcl-1, the Bad-mimetic ABT-737 synergized with ATO in the killing of 2 MM lines. Finally, Noxa expression was enhanced by GSH depletion and inhibited by increasing GSH levels in the cells. Understanding the pattern of BH3-only protein response should aid in the rational design of arsenic-containing regimens.


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