Neoplasia: An International Journal for Oncology Research (Jan 2001)

Killing of Sarcoma Cells by Proapoptotic Bcl-XS: Role of the BH3 Domain and Regulation by Bcl-XL

  • Raj. S. Mitra,
  • Mary A. Benedict,
  • Dalong Qian,
  • Kimberly E. Foreman,
  • Daryoush Ekhterae,
  • Brian J. Nickoloff,
  • Gabriel Nuñez

DOI
https://doi.org/10.1038/sj.neo.7900181
Journal volume & issue
Vol. 3, no. 5
pp. 437 – 445

Abstract

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Kaposi's sarcoma (KS) is the most common tumor affecting AIDS patients with over 20% of these patients afflicted by this disease. Previous studies have demonstrated that KS tumor cells predominantly express the prosurvival protein Bcl-XL compared with Bcl-2. In the current study, we have used an adenoviral vector that expresses Bcl-XS, a functional inhibitor of Bcl-XL, to study the significance of Bcl-XL expression in the KS cell line (SLK) or KS primary cultures. The results demonstrate that 75% to 80% of SLK or KS primary cells were killed by the Bcl-XS containing adenovirus whereas KS cells infected with control adenovirus showed no significant cell death or growth inhibition. Overexpression of Bcl-XL, but not Bcl-2, in SILK cells attenuated apoptosis induced by adenovirus Bcl-XS. Immunoprecipitation experiments revealed that adenoviral Bcl-XS associated with Bcl-XL, but not with Bcl-2. Mutational analysis showed that the α2 helical region of Bcl-XS containing the BH3 motif was critical for killing activity and interaction with Bcl-XL. These results suggest that Bcl-XS is a direct killer and Bcl-XL may act by interacting with and sequestering Bcl-XS. These studies also suggest that targeting Bcl-XL may be of therapeutic benefit for the treatment of tumors that are characterized by inappropriate expression of Bcl-XL.

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