Glucose-deprived HT-29 human colon carcinoma cells are sensitive to verrucosidin as a GRP78 down-regulator.
Glucose deprivation, a feature of poorly vascularized solid tumors, activates the unfolded protein response (UPR) which is a stress-signaling pathway in tumor cells that is associated with the molecular chaperone GRP78 and induction of GRP78 has been shown to protect them against programmed cell death. Thus, targeting glucose-deprived conditions may be a novel strategy in anticancer drug development. Based on that, we established a novel screening program for chaperone modulators that preferentially cytotoxic activity in cancer cells under glucose-deprived conditions. During the course of our screening system, we recently isolated an active compound, 326-2, from Penicillium verrucosum var. cyclopium and identified it as a down-regulator of the grp78 gene. As expected, 326-2 inhibited the expression of the GRP78 promoter under glucose-deprived conditions in a dose-dependent manner with an IC(50) value of 50nM. Furthermore, 326-2 was identified as verrucosidin, a pyrone-type polyketide, by ESI-MS analyses and various NMR spectroscopic methods. We found that verrucosidin prevents UPR-induced expression of protein, such as GRP78, whose expression is induced by glucose-deprived or by 2-deoxyglucose; this effect is not seen under normal growth conditions. The GRP78-inhibitory action of verrucosidin was dependent on strict hypoglycemic conditions and resulted in selective cell death of glucose-deprived HT-29 human colon cancer cells.
Park
Hae-Ryong
HR
Division of Food Science and Biotechnology, Kyungnam University, Masan 631-701, Republic of Korea.
Ryoo
In-Ja
IJ
Choo
Soo-Jin
SJ
Hwang
Ji-Hwan
JH
Kim
Ju-Young
JY
Cha
Mi-Ran
MR
Shin-Ya
Kazuo
K
Yoo
Ick-Dong
ID
D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D015536:Down-Regulation; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose / Q000172:deficiency*; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009183:Mycotoxins / Q000633:toxicity*; D011753:Pyrones / Q000633:toxicity*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009183:Mycotoxins; D011753:Pyrones; C048224:verrucosidin; D005947:Glucose