Geldanamycin induces CHOP expression through a 4-(2-aminoethyl)-benzenesulfonyl fluoride-responsive serine protease

Geldanamycin is a benzoquinone ansamycin, which was originally described as a tyrosine kinase inhibitor. However, subsequent studies have revealed that geldanamycin binds to and inhibits heat-shock protein 90 (Hsp90) activity ¹. Hsp90 is a molecular chaperone involved in the conformational maturation of proteins such as mutated p53, Raf-1, Akt, Bcr-Abl, and ErbB2. It is suggested that agents inhibiting Hsp90 have anti-cancer properties, although the precise molecular mechanisms underlying the anti-cancer effects of geldanamycin are not well understood.

Increasing evidence has suggested that diabetes and neurodegenerative disorders such as Parkinson's and Alzheimer's diseases are related to the disruption of endoplasmic reticulum (ER) function. In response to ER stress, unfolded proteins accumulate and aggregate in the ER, which will trigger many rescuer responses, including the unfolded protein response (UPR) and ER-associated degradation. Interestingly, geldanamycin has been shown to upregulate ER chaperones and the expression of CHOP ². Moreover, Hsp90 associates with PERK and IRE1α, ER-resident trans-membrane protein kinases involved in ER stress response ³. These observations suggest that Hsp90 is involved in ER stress response and may play an important role in ER stress-related diseases. Therefore, we investigated the potential mechanism by which geldanamycin affects ER stress using the L929 fibroblastoma cell line.

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