Prunustatin A, a Novel GRP78 Molecular Chaperone Down-regulator Isolated from Streptomyces violaceoniger

Abstract

In the course of our screening program for regulators of a molecular chaperone GRP78 expression, we isolated a novel inhibitor of GRP78 expression, designated as prunustatin A, from Streptomyces violaceoniger 4521-SVS3. The structure of prunustatin A was determined by a series of NMR analyses to be an oxidized type of the neoantimycin family. Prunustatin A inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells accompanied by global cell death without showing cytotoxicity under normal nutrient condition.Keywords molecular chaperone, GRP78, glucose deprivation, prunustatin GRP78 acts as a molecular chaperone in the endoplasmic reticulum (ER) to promote protein folding. The enhancement of ER stress response has been proven to play a role in mechanisms of resistance to chemotherapy and hypoglycemic stress in solid tumor [1], while the reduction of ER stress response is involved in the pathology of central nervous diseases such as Alzheimer's and Parkinson's diseases [2]. The ER stress response causes an increase in gene expression of a number of ER chaperones such as GRP78/Bip and GRP94 [3]. Thus, substances that directly, either down-or up-regulate grp78 transcription are expected to be promising drugs for the treatment of cancer and Alzheimer's disease, respectively. In the course of our screening program for regulators of GRP78/Bip molecular chaperone expression, we isolated versipelostatin [4] by employing a reporter gene assay system under the control of the GRP78 promoter. Further screening resulted in the isolation of a novel inhibitor of GRP78 expression, designated as prunustatin A (1, Figure 1), a new member of neoantimycin [5] family from an actinomycete identified as Streptomyces violaceoniger 4521-SVS3. In this paper, we report the fermentation of the producing organism and the isolation, physicochemical properties, structure elucidation and brief biological activities of prunustatin A.The prunustatin producing strain was isolated from a soil sample collected on Kumejima island in Okinawa

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

“…Examples are arctigenin [167], deoxyverrucosidin [168], efrapeptin J [169], analogs of JBIR [170], piericidin A [171], prunustatin A [172], pyrvinium [173], rottlerin [174], valinomycin [175], and versipelostatin [176]. Collectively, these compounds are considered GRP78 downregulators, because they were shown to block the adaptive induction of GRP78 transcription in response to hypoglycemia.…”

The Molecular Chaperone GRP78/BiP in the Development of Chemoresistance: Mechanism and Possible Treatment

“…Administration of EGCG has shown re-gain of sensitivity to the topoisomerase inhibitor etoposide in breast cancer cells (Ermakova et al, 2006). Moreover it has been shown that several cytotoxins inhibit GRP78 either by direct cleavage, like Subtilase AB5 derived from E. coli (Paton et al, 2006), or reducing its expression levels like Versipelostatin (derived from Streptomyces versipellis ; Matsuo et al, 2009) or Prunustatin A, a compound isolated from Streptomyces violaceusniger (Umeda et al, 2005). …”

Rare Streptomyces N-Formyl Amino-salicylamides Inhibit Oncogenic K-Ras

“…Planar structures for SW-163A ( 9 ) and SW-163B ( 10 ) were reported in 2001 9 from a Japanese soil Streptomyces sp. (SNA15986), while the planar structures for prunustatin A ( 11 ), and JBIR-04 ( 12 ) and JBIR-05 ( 13 ), were reported in 2005 10 and 2007 11 respectively from the Okinawan soil Streptomyces violaceoniger (4521-SVS3), as down-regulators of the molecular chaperone GRP-78. The absolute configurations of 9 and 11 were subsequently determined in 2007 12 by chemical degradation and derivatization.…”