Figure 6

The proposed potential mechanisms of heat shock protein 90 (HSP90) inhibition lethality in bladder carcinoma cells. This schematic diagram shows that HSP90 inhibitors can substantially alter cellular protein levels directly or indirectly through inhibition of HSP90 leading to rapid ubiquitinylation and degradation of oncogenic client kinases and proteins, or through induction of genetic and epigenetic regulation of gene expression leading to changes of protein levels. These proteins with altered expression are involved in the intracellular signaling pathways of cell cycle progression, apoptotic cell death, DNA damage repair, oxidative stress, autophagy regulation, and endoplasmic reticulum (ER) stress, which are all implicated in cancer cell death. Such a mechanism may serve to integrate the roles of proteasomal degradation, genetic modulation, and epigenetic modification in culmination in misregulating cellular protein expression and cell death, which may underlie the mechanism of HSP90 inhibitor-mediated protein level alteration and cell killing in bladder cancer cells. See the text for details. ROS, reactive oxygen species.