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Apoptosis of Breast Cancer Cells by D‐Threo‐PDMP and cis‐Platin: Translational and Transcriptional Regulation of Glycosyltransferase Genes
Author(s) -
Basu Subhash,
Loucks Audrey J,
Dang Michelle E,
Blasco Michael A,
Kang Jennifer,
Ma Rui,
Basu Manju,
Moskal Joseph R,
Banerjee Sipra
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.526.19
Subject(s) - ceramide , cancer cell , intracellular , apoptosis , glycosphingolipid , biology , signal transduction , microbiology and biotechnology , biochemistry , chemistry , cancer , genetics
The functions of glycosphingolipids on the eukaryotic cell membranes during the onset of oncogenic processes and cell death are not well understood. Inhibitors of glycosphingolipid biosynthesis (L‐PPMP and D‐PDMP) and DNA‐biosynthesis inhibitor (cis‐platin) were recently found to trigger apoptosis in human breast carcinoma cells (SKBR‐3, MCF‐7, and MDA‐468) through either intrinsic or extrinsic apoptotic pathways. These anti‐cancer inhibitors increase ceramide concentration. Apoptotic effects in these cells were determined by activationof caspases (‐3, ‐8, and ‐9) and fluorescent studies using PS‐binding PSS‐380 dye, and intracellular membrane‐binding AKS‐O dye. A time‐dependent scrambling of intracellular membranes was observed after treatment with D‐PDMP upto 6‐ hours. The neolacto‐series glycolipid (SA‐Le X) is distributed mostly on the outer lamella of plasma membranes of human metastatic breast cancer cells. The direct analyses of these glyco‐molecules suggest they alter their structures during the onset of oncogenic processes. Regulation of glycosyltransferase (GLTs) activities involved in the biosynthesis of SA‐Le X is reported in cells treated with L‐PPMP. DNA‐microarrays designed for screening over 340 Glyco‐related genes, transcriptional up‐regulation of several GLTs (in the biosyntheses of Sialo‐Le X and Sialo‐Le a ) was observed with L‐PPMP. GLT‐ activities and gene expressions will be compared with the cells treated with D‐PDMP. Down‐regulation of GLT activities and up‐regulation of some GLT mRNA suggest a tight regulation of these enzymes by signal transduction pathways. 11