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Post-translational and transcriptional regulation of glycolipid glycosyltransferase genes in apoptotic breast carcinoma cells: VII. Studied by DNA-microarray after treatment with l-PPMP

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Abstract

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 were recently found to trigger apoptosis in many carcinoma including breast cancer SKBR-3, MCF-7, and MDA-468 cells through either intrinsic or extrinsic apoptotic pathways as we previously reported. These anti-cancer inhibitors could increase ceramide concentration by blocking functions of glycolipid glycosyltransferases (GLTs). In this study, using a novel fluorescent dye (ASK-0) revealed the damage of cell organelle membranes by an inhibitor of glucosylceramide biosynthesis (L-PPMP). A highly drug- and cell-dependent regulation of MAPKs was also found by cis-platin and L-PPMP when inducing apoptosis in SKBR-3, MCF-7, and MDA-468 cells. A dose and time-dependent regulation of GLTs were investigated by enzymatic assay and DNA microarray analyses. These GLTs are involved in biosynthesis of LeX and sialosyl-LeX (neolactosyl-ceramide series) such as GalT-4 (UDP-Gal: LcOse3cer β−galactosyltransferase, GalT-5 (UDP-Gal: nLcOse4Cer α1, 3galactosyltransferase, FucT-3 (GDP-Fucose: LM1 α1, 4fucosyltransferase). A similar effect was observed with the GLTs involved in the biosyntheses of Gg-series gangliosides, such as SAT-4 (CMP-NeuAc: GgOse4Cer α2, 3sialyltransferase, and SAT-2 (CMP-NeuAc: GM3 α2, 8sialyltransferase). The glycol-related gene DNA-microarrays also suggested the transcriptional regulation of several GLTs involved in the biosynthesis of neolactosylceramide containing cell-surface antigens in these apoptotic breast carcinoma cells. In the early apoptotic stages (2 to 6 h after L-PPMP treatment) in addition to GlcT-1 gene, several genes (βGalTs and βGlcNAcTs) in the SA-Lea pathway were stimulated.

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Abbreviations

GSLs:

Glycosphingolipids

GLTs:

glycolipid glycosyltransferases

GalT:

galactosyltransferases

SAT:

sialyltransferases

FucT:

fucosyltransferases

GlcT:

glycosyltransferase

l-PPMP:

l-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol

d-PDMP:

d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol

SA-LeX :

sialyl-fucosyl-neolactotetraosyl-ceramide

cis-Platin:

cis-diamino-dichloro platinum

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Acknowledgments

This article was written based on research supported by grants NS-18005 (NIMDS), CA-14764 (NCI) and grants-in-aid from the Bayer Corporation Elkhart, Indiana, and Coleman Foundation, Chicago, IL. to S. Basu. We are grateful to Dr. Surendra Gupta of American Radiolabeled Corporation, St. Louis and Sudip Basu of Moraveck Chemicals Corporation, Brea, CA, for providing us radioactive precursor chemicals need for this project. We are thankful to Professor Bradley Smith of the University of Notre Dame for his newly synthesized PSS-380 and AKS-0 dyes used for phosphatidylserine-binding and mitochondrial and Golgi-membrane scrambling studies. Our special thanks to Professor Jen-ichi Inokuchi of Hokkaido. University, Hokkaido, Japan, for providing us gift samples of chemically synthesized L-/D-PPMP and L-/D-PDMP used as apoptotic agents. We gratefully acknowledge the editorial help of Ms. Dorisanne Nielsen, and Christopher Thomas during preparation of this manuscript.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The University of Notre Dame, Notre Dame, IN, 46556, USA

    Rui Ma, N. Matthew Decker, Vesta Anilus, James R. Johnson, Manju Basu & Subhash Basu

  2. The Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, IL, 60201, USA

    Joseph R. Moskal & Joseph Burgdorf

  3. Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH, 44129, USA

    Sipra Banerjee

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  1. Rui Ma
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Correspondence to Subhash Basu.

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Ma, R., Matthew Decker, N., Anilus, V. et al. Post-translational and transcriptional regulation of glycolipid glycosyltransferase genes in apoptotic breast carcinoma cells: VII. Studied by DNA-microarray after treatment with l-PPMP. Glycoconj J 26, 647–661 (2009). https://doi.org/10.1007/s10719-008-9219-4

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