Arsenic is a well-documented human
carcinogen associated with
cancers of the skin, lung, liver, and bladder. Interestingly,
arsenic has also been used as an effective chemotherapeutic agent in the treatment of certain human
cancers. However, the mechanisms by which
arsenic induces proliferation of
cancer cells or
cancer cell death are not well understood. We found that exposure of JB6 P+ cells to low concentrations of
arsenic induces cell transformation, whereas higher concentrations of
arsenic induce cell apoptosis.
Arsenite induces phosphorylation of extracellular signal-regulated
protein kinases (Erks) and c-Jun NH(2)-terminal
kinases (JNKs).
Arsenite-induced Erk activation was markedly inhibited by introduction of dominant-negative Erk2 into cells, whereas expression of dominant-negative Erk2 did not inhibit JNKs or
mitogen-activated protein kinase Erk
kinase 1/2. Furthermore,
arsenite-induced cell transformation was blocked in cells expressing dominant-negative Erk2. In contrast, overexpression of dominant-negative JNK1 increased cell transformation even though it inhibited
arsenite-induced JNK activation.
Arsenic also induced
AP-1 and
nuclear factor kappa B (
NF-kappaB) activation. Blocking
NF-kappaB activation by dominant-negative inhibitory kappa Balpha inhibited
arsenic-induced apoptosis and enhanced
arsenic-induced cell transformation.
Arsenic induced activation of JNKs at a similar dose range that was effective for induction of apoptosis in JB6 cells. In addition, we found that
arsenic did not induce p53-dependent transactivation. Similarly, apoptosis induction was not different between p53 wild-type (p53(+/+)) or p53-deficient (p53(-/-)) cells. In contrast,
arsenic-induced apoptosis was almost totally blocked by expression of a dominant-negative mutant of JNK. Taken together with previous findings that p53 mutations are involved in approximately 50% of all human
cancers and nearly all chemotherapeutic agents kill
cancer cells mainly by apoptotic induction, we suggest that
arsenic may be a useful agent for the treatment of
cancers with p53 mutations. These results suggest that the activation of Erks is required for
arsenic-induced cell transformation, whereas the activation of JNKs and
NF-kappaB is involved in
arsenic-induced apoptosis of JB6 cells.