27 Studies on the inhibitor of molecular chaperone GRP78 expression, versipelostatin
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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 versipelostatin from Streptomyces versipellis 4083-SVS6 as a down-regulator of the grp78 gene. The structure of versipelostatin (C_<61>H_<94>O_<17>) was elucidated on the basis of spectral analyses including 2D NMR (HMQC, DQF-COSY, HMBC) to be a 17-membered macrocyclic compound consisting of an α-acyltetronic acid and sugar moieties. Although, α-acyltetronic acid derivatives such as kijanimicin, tetrocarcins, and teronothiodin were reported, the 17-membered macrocyclic skeleton involving the α-acyltetronic acid moiety in versipelostatin was the first example so far. In the evaluation system we employed, versipelostatin reduced this reporter gene expression at the IC_<50> value of 5μM. Versipelostatin exhibited limited cytotoxic effects against various cancer cell lines. Versipelostatin specifically inhibited the induction of endogenous GRP78 elicited by glucose starvation and 2-deoxyglucose (2-DG) treatment. Versipelostatin, glucose starvation and 2-DG treatment alone did not induce cell death in cancer cells. To the contrary, vigorous cell death was induced by the co-treatment of versipelostatin with glucose starvation or 2-DG in accordance to the decreased level of GRP78. Thus, it is expected that versipelostatin would be a promising cancer chemotherapeutic agent against solid tumor.
