Selective Cytotoxic Activity of Valinomycin against HT-29 Human Colon Carcinoma Cells via Down-Regulation of GRP78

• Published in: Biological & Pharmaceutical Bulletin Vol. 29; no. 4; pp. 817 - 820
• Main Authors: Ryoo, In-Ja, Park, Hae-Ryong, Choo, Soo-Jin, Hwang, Ji-Hwan, Park, Young-Min, Bae, Ki-Hwan, Shin-Ya, Kazuo, Yoo, Ick-Dong
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.04.2006; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Antibiotics, Antineoplastic; Apoptosis - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Down-Regulation - drug effects; endoplasmic reticulum stress; Genes, Reporter; Glucose - deficiency; GRP78; Heat-Shock Proteins - genetics; HT-29; HT29 Cells; Humans; Luciferases - genetics; Molecular Chaperones - genetics; Plasmids - genetics; Transfection; unfolded protein response; valinomycin; Valinomycin - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.29.817

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.