Is DPMS a contributing factor in Tunicamycin‐induced unfolded protein response and shuts down tumor angiogenesis?

Mannosylphopsho dolichol synthase (DPMS) is down stream of N‐acetylglucosamiyl 1‐phosphate transferase (GPT) in the dolichol cycle of asparagine‐linked (N‐linked) protein glycosylation. DPMS is catalytically upregulated by phosphorylation and the product, dol‐p‐man has been claimed to activate the GPT. We have observed that Tunicamycin‐induced unfolded protein response ( upr ) inhibits angiogenesis and consequently the breast tumor growth. There is also a quantitative loss of DPMS activity much earlier in the apoptotic process. Our objective was to evaluate how DPMS contributes to upr ‐mediated cell cycle arrest and apoptosis. The results suggested that both DPMS protein and mRNA remained unaltered in Tunicamycin‐treated cells, but the phospho‐DPMS was reduced. To evaluate it further, we have isolated a DPMS overexpressing and a shRNA knockdown clones and observed that (i) high DPMS activity in the overexpressing clone contributes significantly to protein N‐glycosylation and angiogenesis; and (ii) cells were protected from Tunicamycin. On the other hand, the DPMS knockdown cells were much more vulnerable to Tunicamycin and inhibited angiogenesis by slowing down the cell proliferation. We thus, conclude that non‐functional DPMS contributes to the development of upr which slows down cellular proliferation. Supported by NIH/NCRR/RCMI G12‐RR03035 (KB) and Susan G. Komen for the Cure BCTR06582.