Regulation Of Cell Death Apoptotic Pathways By Nitric Oxide In Cancer: Reversal Of Drug/Immune Resistance.
Tumor cells develop several mechanisms to avoid cell death by various unrelated cytotoxic agents. We have identified one such gene regulatory mechanism that inhibits, in large part, the cell death apoptotic pathways. This dysregulated mechanism is the result of several inter-related gene products that form a loop and consist of the NF-κB/Snail/YY1/RKIP/PTEN. The gene product expressions in this loop regulate the resistance to both chemotherapeutic drugs and cytotoxic immune lymphocytes/ligands. Briefly, the expressions and activities of NF-κB, Snail and YY1 are upregulated whereas the expressions and the activities of RKIP and PTEN are downregulated. The upregulated gene products are involved in the cell survival and growth and the expression of anti-apoptotic gene products; however, the downregulated gene products are involved in the inhibition of cell survival and anti-apoptotic gene products. The modulation of each of the gene products in the loop is sufficient to reverse resistance. We have found that treatment of tumor cells with high levels of NO donors resulted in the downregulation of the expression of NF-κB, Snail and YY1 while upregulation of RKIP and PTEN. Treatment with NO inhibited NF-κB, Snail and YY1 via s-nitrosylation. As repressors, their inhibition resulted in the upregulation of RKIP and PTEN. Subsequently, several anti-apoptotic gene products are inhibited by NO treatment as well as modifying the integrity of the mitochondria. Hence, treatment of resistant tumor cells with NO resulted in both the chemo and immunosensitization of tumor cells to apoptosis, in vitro and in vivo. The findings suggested the important role of NO donors as potential therapeutic sensitizing agents to reverse resistance.
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, USA.
Benjamin
B
Bonavida
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D006801:Humans; D009363:Neoplasm Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D009569:Nitric Oxide / Q000276:immunology*
D009363:Neoplasm Proteins; D009569:Nitric Oxide