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Protein N‐glycosylation is an Excellent Target for Developing Novel Breast Cancer Therapeutics
Author(s) -
Baksi Krishna,
Banerjee Aditi,
Katiyar Usha,
Banerjee Dipak
Publication year - 2015
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.29.1_supplement.890.9
Subject(s) - angiogenesis , cancer research , tunicamycin , matrigel , glycosylation , cell growth , microbiology and biotechnology , n linked glycosylation , chemistry , metastasis , cancer , glycoprotein , biology , apoptosis , unfolded protein response , medicine , biochemistry , glycan
The hallmark of cancer follows the core principles of sustainability to proliferative signaling, ability to evade growth suppressors, ability to resistance cell death, ability to enable replicative immortality, angiogenesis induction, and activating invasion and metastasis. Angiogenesis includes endothelial cell migration, capillary budding, establishment of capillary loops, and neovascular remodeling. Asparagine‐linked (N‐linked) glycoproteins have been found to play an important role in angiogenesis. We have shown earlier that cAMP‐related stimuli upregulate angiogenesis by enhancing N‐glycosylation of cellular glycoproteins (e.g., eFactor VIIIc) due to accelerated synthesis and turnover of Glc3Man9GlcNAc2‐PP‐Dol (i.e., lipid‐linked oligosaccharide), and as a result of phosphorylation activation of mannosylphospho dolichol synthase (DPMS). This led us to hypothesize that N‐glycosylation would be an excellent target for developing new generation anti‐cancer therapeutics. Our results support inhibiting N‐glycosylation causes an accumulation of un‐ or mis‐folded proteins in the ER and develops “ER stress”. The result is cell cycle arrest, and induction of apoptosis. Tunicamycin is effective against both in vitro and in vivo (Matrigel™ implants in nude mice) angiogenesis and cannot be reversed by VEGF. In addition, it prevents breast tumor progression ~55‐65% in 3 weeks in athymic nude mice. Supported in part by grants from NIH/NIMHD 2G12MD007583 (KB) and Susan G. Komen for Cure BCTR0600582 (DKB).