Research article summary (published 29 Nov 2009):

Annexin-A7 protects normal prostate cells and induces distinct patterns of RB-associated cytotoxicity in androgen-sensitive and -resistant prostate cancer cells.

Full Abstract

The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/-)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicityin androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased low-molecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC.

Author information

Author/s: Torosyan, Yelizaveta (Y); Simakova, Olga (O); Naga, Shanmugam (S); Mezhevaya, Katerina (K); Leighton, Ximena (X); Diaz, Juan (J); Huang, Wei (W); Pollard, Harvey (H); Srivastava, Meera (M);

Affiliation: Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Uniformed Services University of Health Sciences School of Medicine, Bethesda, MD 20814, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Dec; vol 125 (issue 11) : pp 2528-39

Dates: Created 2009/10/05; Completed 2009/11/06;

PMID: 19610065, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adenoviridae - genetics Annexin A7 - pharmacology Blotting, Western Cell Cycle - drug effects Cell Proliferation - drug effects DNA, Neoplasm - genetics Drug Resistance, Neoplasm Epithelial Cells - drug effects; metabolism Gene Expression Profiling Genetic Vectors Humans Male

Male Neoplasms, Hormone-Dependent - genetics; metabolism; pathology Oligonucleotide Array Sequence Analysis Phosphorylation Prostate - drug effects; metabolism Prostatic Neoplasms - genetics; metabolism; pathology Receptors, Androgen - metabolism Retinoblastoma Protein - metabolism Transfection Tumor Cells, Cultured Tumor Markers, Biological - genetics; metabolism Tumor Suppressor Proteins - pharmacology

Associated Chemicals: AR protein, human (0) ; Annexin A7 (0) ; DNA, Neoplasm (0) ; Receptors, Androgen (0) ; Retinoblastoma Protein (0) ; Tumor Markers, Biological (0) ; Tumor Suppressor Proteins (0)

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