| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 86 === According to epidemiology studies, arsenic compounds are recognized
as human carcinogens. The cellular and molecular mechanism(s) of
arsenic carcinogenicity is yet not clear. Human population with
chronic arsenic exposure through drinking water ingestion show
increased frequencies on chromosome aberrations and sister chromatid
exchanges and increased risks for cancers of skin, lung, liver,
bladder, and prostate. Although arsenite-induced cell morphological
transformation is associated with cytogenetic alterations, the
underlying mechanisms of arsenite-induced cytogenetic alterations
remain obscure. Arsenite is inactive or too weak to induce gene point
mutations, arsenite-induced cytogenetic alterations may play a
crucial role in arsenic carcinogenicity.
Previous studies have shown that treatment of 10 - 80 uM arsenite for
4 h induces chromosome aberrations, sister chromatid exchanges, and
micronuclei via the induction of oxidative stress. In this thesis,
evidence has shown that chronic (0 - 5 uM for 24 h) and acute (10 -
40 uM for 24 h) arsenite treatment resulted in different cytogenetic
alterations. Chronic treatment with arsenite induced kinetochore-
positive micronuclei (K+-MN) and c-anaphases probably via the
alteration of mitosis, whereas acute treatment induced
kinetochore-negative micronuclei (K--MN) and chromatid breaks
probably via the induction of oxidative stress.
Further analysis of arsenite''s effects on mitosis progression has
shown that treatment of HFW cells at G2 phase with 5 uM arsenite
resulted in the accumulation of cyclin B and inhibition of cdc25C
phosphorylation and cdc2 dephosphorylation and led to G2 arrest.
Arsenite also induced mitotic spindle derangement and chromosome
segregation alterations and resulted in mitotic arrest. These
deleterious effects of arsenite might lead to chromosome loss
and chromosome instability in daughter cells.
C-anaphases, a type of abnormal chromosome segregation, may lead to
anuploidy. Treatment of HFW cell wit 5 mM arsenite for 18 h could
induce c-anaphases. Treatment of nocodazole- or taxol-induced mitotic
cells with arsenite also induced c-anaphases. These results
indicate that arsenite could interfere with chromosome segregation
during mitosis. Staurosporine, a protein kinase inhibitor, was found
to reduce arsenite-induced c-anaphases, indicating that arsenite
might disturb the cascades of cellular protein phosphorylation and
dephosphorylation and result in abnormal chromosome segregation.
These results showed that arsenite might alter protein
phosphorylation status and disturb the function of mitosis
regulating proteins which might result in abnormal mitosis and lead
to the induction of chromosome instability. Chromosome instability is
important and possibly essential in multistep carcinogenesis.
Arsenite may thus invovled the initiation, promotion, and
progression steps in carcinogenesis.
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