HSP90: A Key Player in Metal-Induced Carcinogenesis?

Abstract

Three extensively used metals, cadmium, chromium and nickel, are established human carcinogens. The elucidation of the molecular and cellular mechanisms underlying the carcinogenicity of these metals has centered mostly on the signalling pathways that regulate cellular growth, differentiation and death. Unfortunately, our understanding of the involvement of these pathways in metal-induced carcinogenesis is still very incomplete. More recently, research has extended to include the impact of these metals on mechanisms not traditionally associated with cancer, but that are now increasingly viewed as playing a critical role in carcinogenesis. Among them is the stress response, a highly conserved mechanism employed by all cells for protection against protein damage. Indeed, all three metals induce proteotoxic stress, which warrants following this line of research. The present chapter will critically review published studies on the impact of carcinogenic metals on the expression of the heat shock protein 90 family (HSP90), one of the protein families that mediate the stress response. HSP90 has been consistently found to be overexpressed in many types of cancer and, significantly, HSP90 overexpression has been correlated with increased tumor growth, metastatic potential and resistance to chemotherapy.