Received for publication June 20, 2007.
Revised August 15, 2007.
Accepted for publication August 16, 2007.

Geranylgeranylacetone, an Inducer of HSP70, Elicits Unfolded Protein Response and Coordinates Cellular Fate Independently of HSP70

Abstract

Geranylgeranylacetone (GGA), an anti-ulcer agent, has the ability to induce 70 kDa heat shock protein (HSP70) in various cell types and to protect cells from apoptogenic insults. However, little is known about effects of GGA on other HSP families of molecules. We found that, at concentrations 100 µM, GGA caused selective expression of 78 kDa glucose-regulated protein (GRP78), a HSP70 family member inducible by endoplasmic reticulum (ER) stress, without affecting the level of HSP70 in various cell types. Induction of ER stress by GGA was also evidenced by expression of another endogenous marker CHOP, decreased activity of ER stress-responsive alkaline phosphatase and unfolded protein response (UPR) including activation of the ATF6 pathway and the IRE1 - XBP1 pathway. Incubation of mesangial cells with GGA caused significant apoptosis, which was attenuated by transfection with inhibitors of caspase-12; i.e., a dominant-negative mutant of caspase-12 and MAGE-3. Dominant-negative suppression of IRE1 or XBP1 significantly attenuated apoptosis without affecting the levels of CHOP and GRP78. Inhibition of c-Jun N-terminal kinase, the molecule downstream of IRE1, by SP600125 did not improve cell survival. Blockade of ATF6 by AEBSF enhanced apoptosis by GGA, and it was correlated with attenuated induction of both GRP78 and CHOP. Overexpression of GRP78 or dominant-negative inhibition of CHOP significantly attenuated GGA-induced apoptosis. These results suggested that GGA triggers both proapoptotic (IRE1 - XBP1, ATF6 - CHOP) and antiapoptotic (ATF6 - GRP78) UPR and thereby coordinates cellular fate even without induction of HSP70.

Key words: Regulation - transcriptional, Mechanisms of cell killing/apoptosis