AKT upregulates B-Raf Ser445 phosphorylation and ERK1/2 activation in prostate cancer cells in response to androgen depletion
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AbstractUpregulated ERK1/2 activity is often correlated with AKT activation during prostate cancer (PCa) progression, yet their functional relation needs elucidation. Using androgen-deprived LNCaP cells, in which ERK1/2 activation occurs in strong correlation with AKT activation, we found that AKT-mediated B-Raf regulation is necessary for ERK1/2 activation. Specifically, in response to androgen deprivation, Ala upregulated B-Raf phosphorylation at Ser445 without affecting A-Raf or C-Raf-1. This effect of AKT was abolished by Arg25 to Ala mutation or truncating (Delta 4-129) the pleckstrin homology domain of AKT, indicating that the canonical AKT regulation is important for this signaling. Intriguingly, although a constitutively active AKT containing N-terminal myristoylation signal could sufficiently upregulate B-Rat phosphorylation at Ser445 in LNCaP cells, subsequent MEK/ERK activation still required hormone deprivation. In contrast, AKT activity was sufficient to induce not only B-Raf phosphorylation but also MEK/ERK activation in the hormone refractory LNCaP variant, C4-2. These data indicate that androgen depletion may induce MEK/ERK activation through a synergy between AKT-dependent and -independent mechanisms and that the latter may become deregulated in association with castration resistance. In support, consistent AKT-mediated B-Rat regulation was also detected in a panel of PCa lines derived from the cPten(-/-) L mice before and after castration. Our results also demonstrate that AKT regulates androgen receptor levels partly via the Raf/MEK/ERK pathway. This study reveals a novel crosstalk between ERK1/2 and AKT in PCa cells. (C) 2013 Elsevier Inc. All rights reserved.
All Author(s) ListHong SK, Jeong JH, Chan AM, Park JI
Journal nameExperimental Cell Research
Detailed descriptionTo ORKTS: doi: 10.1016/j.yexcr.2013.05.008
Volume Number319
Issue Number12
Pages1732 - 1743
LanguagesEnglish-United Kingdom
KeywordsAKT; Androgen withdrawal; B-Raf; ERK1/2; Prostate cancer
Web of Science Subject CategoriesCell Biology; CELL BIOLOGY; Oncology; ONCOLOGY

Last updated on 2021-11-05 at 00:15