Alterations in β‐catenin expression and localization in prostate cancer

Whitaker, Hayley C.; Girling, Joanne; Warren, Anne Y.; Leung, Hing Y.; Mills, Ian G.; Neal, David E.

doi:10.1002/pros.20780

Cited by 63 publications

(56 citation statements)

References 19 publications

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“…In our series of patients, high Gleason score significantly correlated with low expression of PKCd and high expression of active b-catenin, AurKA, phosphoGSK3b Ser9 , and Mcl-1. Several studies have associated aberrant expression or high nuclear and cytoplasmic expression of b-catenin with high Gleason score tumors (33)(34)(35)(36)(37), yet others did not find an association between b-catenin expression and the Gleason score (38)(39)(40). We are the first to show a strong correlation between high active b-catenin immunohistochemical expression and high Gleason score prostate tumors.…”

Section: Discussionmentioning

confidence: 48%

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Flores

Castilla

Gasca

et al. 2016

Molecular Cancer Therapeutics

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Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCd silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCd seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/b-catenin pathway. PKCd silencing induces activation of Wnt/b-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3b inactivation and consequently in the stabilization of b-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/b-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCd. Finally, we observe that high Gleason score prostate tumors lose PKCd expression and this correlates with higher activation of b-catenin, inactivation of GSK3b, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/b-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCd expression.

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Section: Discussionmentioning

confidence: 48%

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Flores

Castilla

Gasca

et al. 2016

Molecular Cancer Therapeutics

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“…The patient population was identical to the one previously described (18). The tumor grade was classified by a uropathologist (A.W.)…”

Section: Methodsmentioning

confidence: 99%

“…Staining was visualized with diaminobenzidine tetrahydrochloride (Vector Laboratories) and the nucleus was counterstained lightly with hematoxylin (Vector Laboratories). Tissues were mounted and visualized as described (18).…”

Section: Methodsmentioning

confidence: 99%

LYRIC/AEG-1 Is Targeted to Different Subcellular Compartments by Ubiquitinylation and Intrinsic Nuclear Localization Signals

Thirkettle

Girling

Warren

et al. 2009

Clinical Cancer Research

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139

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Purpose: LYRIC/AEG-1 has been reported to influence breast cancer survival and metastases, and its altered expression has been found in a number of cancers. The cellular function of LYRIC/ AEG-1has previously been related to its subcellular distribution in cell lines. LYRIC/AEG-1contains three uncharacterized nuclear localization signals (NLS), which may regulate its distribution and, ultimately, function in cells. Experimental Design: Immunohistochemistry of a human prostate tissue microarray composed of 179 prostate cancer and 24 benign samples was used to assess LYRIC/AEG-1 distribution. Green fluorescent protein-NLS fusion proteins and deletion constructs were used to show the ability of LYRIC/AEG-1NLS to target green fluorescent protein from the cytoplasm to the nucleus. Immunoprecipitation and Western blotting were used to show posttranslational modification of LYRIC/AEG-1NLS regions. Results: Using a prostate tissue microarray, significant changes in the distribution of LYRIC/ AEG-1 were observed in prostate cancer as an increased cytoplasmic distribution in tumors compared with benign tissue. These differences were most marked in high grade and aggressive prostate cancers and were associated with decreased survival. The COOH-terminal extended NLS-3 (amino acids 546-582) is the predominant regulator of nuclear localization, whereas extended NLS-1 (amino acids 78-130) regulates its nucleolar localization. Within the extended NLS-2 region (amino acids 415-486), LYRIC/AEG-1 can be modified by ubiquitin almost exclusively within the cytoplasm. Conclusions: Changes in LYRIC/AEG-1 subcellular distribution can predict Gleason grade and survival. Two lysine-rich regions (NLS-1 and NLS-3) can target LYRIC/AEG-1 to subcellular compartments whereas NLS-2 is modified by ubiquitin in the cytoplasm.

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“…jci.org Volume 126 Number 5 May 2016 infrequent in PCa, and enhanced WNT/β-catenin signaling, as indicated by elevated nuclear β-catenin staining, has been inconsistently found in clinical PCa (56)(57)(58)(59)(60). However, it has become clear that nuclear β-catenin staining is not a sensitive indicator of WNT/β-catenin pathway activation and that robust biomarkers and mechanisms of WNT signaling are needed to fully elucidate the role of this pathway in PCa (47)(48)(49)(50)(51)(52)(53)(54).…”

Section: 5mentioning

confidence: 99%

SOX9 drives WNT pathway activation in prostate cancer

Ma¹,

Ye²,

He³

et al. 2016

Journal of Clinical Investigation

149

126

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Alterations in β‐catenin expression and localization in prostate cancer

Abstract: A loss of nuclear beta-catenin is the most consistent feature in prostate cancer rather than absolute levels of expression. We also suggest that variation in immunohistochemical protocols may explain variations in the reported literature.

Cited by 63 publications

References 19 publications

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

LYRIC/AEG-1 Is Targeted to Different Subcellular Compartments by Ubiquitinylation and Intrinsic Nuclear Localization Signals

SOX9 drives WNT pathway activation in prostate cancer

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