PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells

Abstract

Methylselenol has been implicated as an active metabolite for the anticancer effect of selenium in part through the induction of cancer cell apoptosis. Since inactivation of the AKT/protein kinase B negative regulator gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) 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, although 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 mitochondrial release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by extracellular signal regulated kinases 1 and 2 (ERK1/2) inhibition without further increase in 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. An 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.

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

“…It is well established that HIF-1a is induced both by hypoxia and PI3K pathway in several cell types. 20,42,43 Even though several reports including ours 31,44 showed that selenium compounds could influence PI3K/Akt pathway in various cancer cell lines, this interaction has yet to be addressed under hypoxic conditions. DNA binding of HIF-1a is significantly reduced by MSeA in PAIII and PC-3 cells both in normoxia and hypoxia.…”

“…29,30 A promising anticancer agent methylseleninic acid (MSeA) has been shown to be effective in inhibiting prostate cancer growth in vitro and in TRAMP model. 31,32 However, the potential of MSeA as a therapeutic agent has not been tested in humans, and the underlying mechanism(s) of selenium compounds including MSeA have not been studied in hypoxic conditions.…”

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

“…[190][191][192] In vitro studies suggest that this effect may hinge to some degree on suppression of IκB kinase activation and NF-κB activity, as well as on an amplification of p53 function and a reduction in Akt phosphorylation. [193][194][195][196][197][198][199] This phenomenon may have important ramifications for chemotherapy/radiotherapy. Several years ago, Vadgama and colleagues reported that selenium potentiated the response of a range of human cancer cell lines to adriamycin or taxol in vitro.…”

ERK activation induced by selenium treatment significantly downregulates β/γ-secretase activity and Tau phosphorylation in the transgenic rat overexpressing human selenoprotein M

“…In particular, an inorganic form of this compound, sodium selenite, was shown to increase the p38 and p53 phosphorylation, activating caspaseindependent cell death (11,12). Furthermore, this compound activates anti-apoptotic and the mitogen-activated protein inhibitor (MAPK) pathway to prevent damage to brain tissues and cells (13,14). However, few studies have been conducted to investigate whether selenium treatment and SelM overexpression affects the key regulator of AD pathology using a transgenic rat overexpressing the human SelM (hSelM) gene.…”