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Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells
Author(s) -
Torosyan Yelizaveta,
Simakova Olga,
Naga Shanmugam,
Mezhevaya Katerina,
Leighton Ximena,
Diaz Juan,
Huang Wei,
Pollard Harvey,
Srivastava Meera
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24592
Subject(s) - lncap , du145 , androgen , prostate cancer , cancer research , prostate , apoptosis , chemistry , endocrinology , medicine , cancer , biochemistry , hormone
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.