Carcinogenesis Advance Access published online on April 21, 2005
Carcinogenesis, doi:10.1093/carcin/bgi094
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1 The Hormel Institute, University of Minnesota, 801 16th St NE, Austin, MN 55912
* To whom correspondence should be addressed. Methylselenol has been implicated as an active metabolite for the anti-cancer effect of selenium in part through the induction of cancer cell apoptosis. Because inactivation of the AKT/PKB negative regulator gene PTEN is common in prostate cancer (PCa), we compared PTEN-wild type DU145 PCa cells (low basal AKT activity) with PTEN-mutant LNCaP PCa cells (high basal AKT activity) for their apoptosis responses to the methylselenol precursor methylseleninic acid (MSeA) and sodium selenite, an inorganic salt. Our results show that LNCaP cells withstood approximately 4 times higher doses of MSeA than DU145 cells, even though they were slightly more sensitive than the latter to selenite-induced apoptosis. Treatment by MSeA modestly attenuated AKT phosphorylation and increased phospho-ERK1/2 in LNCaP cells. Selenite treatment increased the phosphorylation of p53 Ser15 and both kinases, but the selenite-induced apoptosis was not influenced by chemical inhibitors of either kinase. In contrast, PI3K/AKT inhibitors greatly sensitized LNCaP cells to apoptosis induced by MSeA, accompanied by increased mitochondria release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by ERK1/2 inhibition without further increasing cytochrome c release. The general caspase inhibitor z-VAD-fmk completely blocked MSeA-induced apoptosis when both kinases were inhibited, whereas a caspase-8 inhibitor exerted a greater protection than did a caspase-9 inhibitor. Transfection of DU145 cells with a constitutively active AKT increased their resistance to MSeA-induced apoptosis. In summary, AKT played an important role in regulating apoptosis sensitivity of LNCaP and DU145 cells to MSeA. A MSeA-induced activation of ERK1/2 in LNCaP cells also contributed to resistance to apoptosis. However, these kinases did not significantly regulate caspase-mediated apoptosis induced by selenite in LNCaP cells. These findings support the differential involvement of these protein kinase pathways in regulating apoptosis induction by different forms of selenium.
Received December 21, 2004
Revised March 30, 2005
Accepted April 10, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells
Junxuan Lü, E-mail: jlu{at}hi.umn.edu
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