36 新規GRP78転写抑制物質prunustatin Aに関する研究

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GRP78 acts as a molecular chaperone in endoplasmic reticulum (ER) by associating transiently with incipient proteins as they traverse the ER and aiding in their folding and transport. Furthermore, the GRP78 protein is also induced under various stress condition such as glucose starvation, inhibition of protein glycosylation by tunicamycin, perturbation of ER function and protein movement by brefeldin A, and suppression of ER-calcium-ATPase pump by thapsigargin. The enhancement of ER stress response (also known as the unfolded protein response) takes part in the resistant mechanism against chemotherapy and hypoxic stress in solid tumor. The ER stress response causes an increase in gene expression of a number of ER chaperones such as GRP78 and GRP94. Thus, substances that directly down-regulate grp78 transcription are expected to be useful drugs for the treatment of solid tumor. In the course of our screening for inhibitors of luciferase expression, which is regulated under the control of GRP78 promoter, by the treatment of tunicamycin, we isolated a novel compound designated as prunustatin A from Streptomyces violaceoniger 4521-SVS3 as a down-regulator of the grp78 gene. The structure of prunustain A (C_<34>H_<40>N_2O_<12>) was elucidated on the basis of spectral analyses including 2D NMR (HMQC, DQF-COSY, HMBC). Prunustatin A consisted of a 3-formylamino-2-hydroxybezoic acid moiety as a chromophore and 15-membered macrocycles composed of an L-threonine, an L-lactatic acid, a 2R,3R-4-hydroxy-2,2-dimethyl-3-oxo-5-phenylpentanoic acid and a 2S,3S-2-hydroxy-3-methylpentanoic acid moieties. In the evaluation system we employed, prunustatin A reduced this reporter gene expression at the IC_<50> value of 1.9nM. Prunustatin A also completely inhibited the induction of endogenous GRP78 protein induced by 2-deoxyglucose at the concentration of 100nM. Prunustatin A, glucose starvation and 2-DG treatment alone did not induce cell death in cancer cells. However, prunustatin A specifically elicited global cell death when combined with 2-deoxyglucose. Thus, it is expected that prunustatin A would be a promising cancer chemotherapeutic agent against solid tumor.
天然有機化合物討論会の論文
2005-09-15

36 新規GRP78転写抑制物質prunustatin Aに関する研究

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