Inorganic arsenic and human prostate cancer

Abstract

Objective: We critically evaluated the etiologic role of inorganic arsenic in human prostate cancer.

Data sources: We assessed data from relevant epidemiologic studies concerning environmental inorganic arsenic exposure. Whole animal studies were evaluated as were in vitro model systems of inorganic arsenic carcinogenesis in the prostate.

Data synthesis: Multiple studies in humans reveal an association between environmental inorganic arsenic exposure and prostate cancer mortality or incidence. Many of these human studies provide clear evidence of a dose-response relationship. Relevant whole animal models showing a relationship between inorganic arsenic and prostate cancer are not available. However, cellular model systems indicate arsenic can induce malignant transformation of human prostate epithelial cells in vitro. Arsenic also appears to impact prostate cancer cell progression by precipitating events leading to androgen independence in vitro.

Conclusion: Available evidence in human populations and human cells in vitro indicates that the prostate is a target for inorganic arsenic carcinogenesis. A role for this common environmental contaminant in human prostate cancer initiation and/or progression would be very important.

Keywords: AR; DNA methylation; MAP kinase; Ras; androgen-independent; arsenic; carcinogenesis; human malignant transformation; prostate.

Figure 1

Mechanisms of arsenic-induced acquired androgen independence. Abbreviations: AR, androgen receptor; ARE, androgen responsive element; As, arsenic; GF, growth factors; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPK kinase kinase; PSA, prostate-specific antigen. It is known that exposure to arsenic initiates GF receptor signaling and Ras-dependent activation of MEK1/2 and ERK1/2. (A) As prostate cancer progresses to androgen independence, the growth factors production increases. Growth factor signal transduction pathways have been shown to stimulate AR activation. All these growth factors use the Ras/MAPK pathway for a portion of their signal transduction. Binding of GF results in dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The GF receptor activates ras which in turn activates Raf, which phosphorylates and activates MEK, which in turn, phophorylates and activates ERK. Activated MAPK can regulate targets in the cytosol and also translocate to the nucleus causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1, which contribute to proliferation. (B) HER-2/neu promotes phosphorylation of AR at multiple sites even in the presence of very low androgen levels. HER-2/neu indirectly activates MAPK. MAPK might phosphorylate the AR, creating an androgen-independent receptor.