Selective cytotoxic activity of valinomycin against HT-29 Human colon carcinoma cells via down-regulation of GRP78.
Glucose deprivation is a fundamental feature of poorly vascularized solid tumors and leads to activation of the molecular chaperone GRP78, which is associated with the unfolded protein response (UPR), a stress-signaling pathway, in tumor cells. We recently isolated an active compound, M126, that inhibits transcription from a GRP78 promoter reporter construct. M126 was identified as valinomycin by various spectroscopic methods. We found that valinomycin prevents UPR-induced protein expression, such as GRP78 and GRP94. The GRPs-inhibitory action of valinomycin severe hypoglycemic and results in selective cell death of the stressed cancer cells. Our findings demonstrate that GRP78 may be an excellent target for the use of cancer chemotherapy in the treatment of solid tumors.
Ryoo
In-Ja
IJ
Laboratory of Antioxidant, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
Park
Hae-Ryong
HR
Choo
Soo-Jin
SJ
Hwang
Ji-Hwan
JH
Park
Young-Min
YM
Bae
Ki-Hwan
KH
Shin-Ya
Kazuo
K
Yoo
Ick-Dong
ID
D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D017930:Genes, Reporter; D005947:Glucose / Q000172:deficiency; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D014162:Transfection; D014634:Valinomycin / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D014634:Valinomycin; D008156:Luciferases; D005947:Glucose