Effects On Signal Transduction And Apoptosis

The presence of metals can affect signal transduction, especially for genes known to be responsive to the oxidative status of the cell, such as p53. This will, in turn, affect the actions of the cell controlled by these genes. One of the effects most commonly associated with cancer-causing metals is apoptosis. Metals can cause apoptosis via extrinsically (cell receptor) or intrinsically (mitochondrial or DNA damage) mediated mechanisms. Apoptosis can be induced through p53-dependent or p53-independent pathways.49 Chromium (VI) can indirectly induce p53-mediated apoptosis in at least three ways: through direct DNA damage, through activation of mitogen-activated (MAP) kinases upstream of p53, and through the oxidative activation of p53 itself. Reduced forms of chromium or the reactive oxygen species produced by them both have the capacity to damage DNA. Damage, such as DNA strand breaks, activates upstream kinases, such as DNA protein kinase, Ataxia telangiectasia mutated protein kinase, and the Ataxia telangiectasia and rad3+-related protein kinase, all of which are capable of activating p53.50 The binding of chromium (III) and chromium (V) to DNA can result in the activation of MAP kinases, such as c-Jun N-terminal kinase and p38, which, in turn, can activate p53 without DNA damage. Due to the presence of cysteine residues within the protein, p53 is sensitive to and can be activated by changes in oxidative conditions within the cell.51

Arsenic-induced apoptosis is independent of p53 and is mediated through direct mitochondrial damage and MAP kinase activation. Arsenic can cause M-phase cell-cycle arrest and apoptosis in p53-negative cells. Arsenic damages mitochondria via free-radical mechanisms. Activation of either p38 or c-Jun N-terminal kinase subsequently activates growth arrest and DNA damage (GADD) genes. Activation of GADD45 causes arsenic-induced cell-cycle arrest.52

Paradoxically, both apoptosis and the inhibition of apoptosis can be carcinogenic. Generalized apoptosis of a cell population may select for apoptosis-resistant cells. The inhibition of apoptosis may allow for the growth and replication of cells that contain substantial DNA damage, thus perpetuating potentially carcinogenic cell traits. Chromium (VI) appears to do both of these, as it initially activates and later inactivates p53.

Although many of the effects of metals appear to be mediated through free-radical production, this does not explain all of the effects of metals. For example, chromium (VI) is a stronger prooxidant and mutagen than arsenic (III); however, arsenic (III) is a more potent carcinogen. One explanation for this is the differing ways in which inetals affect the signal transduction pathways of cancer-related genes. The nuclear transcription factor kappa-B (NFkB) is known to be up-regulated in many cancers. Arsenic (III) and Cr (VI), both human carcinogens, have been shown to both activate and inactivate NFkB.53 The extent to which activation or inactivation occurs appears to be dependent both on metal concentration and cell type. At levels that are physiologically achievable in vivo (in the low micromolar range), arsenic (III) appears to induce NFkB.

A number of authors have proposed that this activation is due to the production of free radicals. However, three experimental findings indicate that the mechanism may also be independent of oxidation. First of all, the binding of the NFkB protein to DNA, which is necessary for its activity, is reduced when the NFkB protein itself is oxidized. In other words, the NFkB protein is more effective as a transcription factor when it has not been oxidized. Second, chromium (VI) generates more radicals than arsenic (III) but induces NFkB to a lesser extent. Finally, the signal transduction pathways known to control NFkB activation (LPS, IL-1, Toll, CD28) are not activated by oxidative stress. Together, these findings indicate that carcinogenic metals may have mechanisms that are independent of or in addition to free-radical formation, at least with regard to NFkB.54

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