Triterpenoid electrophiles (avicins) suppress heat shock protein-70 and x-linked inhibitor of apoptosis proteins in malignant cells by activation of ubiquitin machinery: implications for proapoptotic activity.

Abstract

Avicins are plant-derived triterpenoid stress metabolites that have both proapoptotic and cytoprotective properties. Avicins induce apoptosis in Jurkat T leukemia cells by targeting mitochondria and release of cytochrome c that occurs in a p53-independent manner. However, postmitochondrial antiapoptotic barriers, such as increased expression of heat shock proteins (Hsp) and X-linked inhibitor of apoptosis proteins (XIAP), frequently exist in cancer cells and often account for resistance to chemotherapy and a poor prognosis. In this article, we show the role of avicins in the activation of stress-regulated ubiquitination and degradation of Hsp70 and XIAP. This is the first report showing the regulation of Hsp70 via the ubiquitin/proteasome pathway. We also show the induction of E3alpha ubiquitin ligase in avicin-treated Jurkat T leukemia cells, and its involvement in the degradation of XIAP. Avicin-mediated suppression of Hsp70 and XIAP was further confirmed in other leukemic/lymphoma cell lines and freshly isolated peripheral blood lymphocytes from Sezary syndrome patients. No change in the Hsp70 and XIAP proteins was observed in peripheral blood lymphocytes from normal donors. We propose that the ability of avicins to induce ubiquitination and regulate the degradation of Hsp70 and XIAP in leukemia cells could have important implications in the treatment of drug-resistant neoplasia and inflammatory disorders.

• Authors: Amos Gaikwad, Ann Poblenz, Valsala Haridas, Chunlei Zhang, Madeleine Duvic, Jordan Gutterman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 5 Pg. 1953-62 (Mar 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15756021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HSP70 Heat-Shock Proteins
• Proteins
• Triterpenes
• Ubiquitins
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human

Topics

• Apoptosis
• Blotting, Western
• HSP70 Heat-Shock Proteins (biosynthesis, metabolism)
• Humans
• Leukemia (pathology)
• Lymphoma (pathology)
• Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sezary Syndrome (pathology)
• Triterpenes (pharmacology)
• Tumor Cells, Cultured
• Ubiquitins
• X-Linked Inhibitor of Apoptosis Protein