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Nickel Compounds Act through Phosphatidylinositol-3-kinase/Akt-Dependent, p70^S6k-Independent Pathway to Induce Hypoxia Inducible Factor Transactivation and Cap43 Expression in Mouse Epidermal Cl41 Cells

¹Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, New York; ²MBR Cancer Center, Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia; and ³Institute for Nutrition Sciences, Chinese Academy of Sciences, Shanghai, China

Nickel compounds are a somewhat unique class of carcinogens. Previous studies have demonstrated that NiCl₂ exposure leads to marked induction of hypoxia inducible factor 1 (HIF-1) in human osteosarcoma and BALB/c 3T3 cells, a transcription factor that has been considered to play an important role in tumor promotion and progression. However, the signal transduction pathways leading to HIF-1 induction are not well understood. The present study indicated that exposure of mouse epidermal Cl41 cells to either Ni₃S₂ or NiCl₂ resulted in activation of phosphatidylinositol 3-kinase (PI-3K), Akt, and p70 S6 kinase (p70^S6k). Inhibition of PI-3K, Akt, and p70^S6k by overexpression of a dominant-negative mutant of PI-3K (p85) impaired nickel-induced HIF-1 transactivation. Furthermore, an overexpression of the dominant-negative Akt mutant (Akt-T308A/S473A) blocked nickel-induced Akt phosphorylation and HIF-1 transactivation, whereas inhibition of p70^S6k activation by pretreatment of cells with rapamycin did not show significant inhibitory effects on HIF-1 transactivation induced by nickel compounds. Consistent with HIF-1 transactivation, inhibition of the PI-3K/Akt pathway by either overexpression of p85 or Akt-T308A/S473A caused dramatic inhibition of Cap43 protein expression induced by nickel compounds, whereas pretreatment of cells with rapamycin did not exhibit inhibition of Cap43 induction. These results demonstrated that nickel compounds induce HIF-1 transactivation and Cap43 protein expression through a PI-3K/Akt-dependent and p70^S6k-independent pathway. This study should help us understand the signal transduction pathways involved in the carcinogenic effects of nickel compounds.

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