Impact of Carcinogenic Chromium on the Cellular Response to Proteotoxic Stress

Abstract

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response-an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.

Keywords: HSP inhibitor; HSP70; HSP90; carcinogenesis; heat shock proteins; hexavalent chromium; occupational lung carcinogen; proteotoxic stress; stress response; unfolded protein response.

Figure 1

The different types of stress associated with the three stages of carcinogenesis. Carcinogenesis has been traditionally divided in three stages: initiation, promotion and progression. Different types of cellular stress have been implicated in these stages. Oxidative stress and reactive oxygen species (ROS) damage proteins and membranes, and induce DNA mutations. Incipient cancer cells at the promotion stage harbor an increasing number of DNA mutations, resulting in dramatically higher levels of mutant proteins that induce proteotoxic stress. Transition to a fully malignant phenotype, i.e., progression, is thought to require chromosomal instability and resulting karyotypic abnormalities, inducing genotoxic stress. Of note, all types of stress indicated (oxidative, proteotoxic and genotoxic) play roles in all three stages of carcinogenesis described above; their relative importance likely differs amongst different types of cancer.