Distinct Effects of Annexin A7 and p53 on Arachidonate Lipoxygenation in Prostate Cancer Cells Involve 5-Lipoxygenase Transcription

Abstract

Tumor suppressor function for Annexin A7 (ANXA7; 10q21) is based on cancer-prone phenotype in Anxa7(+/À) mouse and ANXA7 prognostic role in human cancers. Because ANXA7-caused liposome aggregation can be promoted by arachidonic acid (AA), we hypothesized that the phospholipid-binding tumor suppressor ANXA7 is associated with AA cascade. In a comparative study of ANXA7 versus canonical tumor suppressor p53 effects on AA lipoxygenation pathway in the p53-mutant and androgen-insensitive DU145 prostate cancer cells, both tumor suppressors altered gene expression of major 5-lipoxygenase (LOX) and 15-LOXs, including response to T helper 2 (Th2)-cytokine [interleukin-4 (IL-4)] and endogenous steroids (mimicked by dexamethasone). Wild-type and mutant ANXA7 distinctly affected expression of the dexamethasone-induced 15-LOX-2 (a prostate-specific endogenous tumor suppressor) as well as the IL-4-induced 15-LOX-1. On the other hand, wild-type p53 restored 5-LOX expression in DU145 to levels comparable to benign prostate epithelial cells. Using mass spectrometry of DNA affinity-enriched nuclear proteins, we detected different proteins that were bound to adjacent p53 and estrogen response elements in the 5-LOX promoter in DU145 cells introduced with ANXA7 versus p53. Sex hormone regulator 17-B hydroxysteroid dehydrogenase 4 was identified under p53 introduction, which induced the 5-LOX expression. Meantime, nuclear proteins bound to the same 5-LOX promoter site under introduction of ANXA7 (that was associated with the repressed 5-LOX) were identified as zinc finger proteins ZNF433 and Aiolos, pyrin domaincontaining NALP10, and the p53-regulating DNA repair enzyme APEX1. Thus, ANXA7 and p53 can distinctly regulate LOX transcription that is potentially relevant to the AAmediated cell growth control in tumor suppression.

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

“…The hnRNPK level within the nuclear matrix in particular correlates with the Gleason score in prostate cancer (Barboro et al, 2009). Hence, the nuclear hnRNPK at the ANXA7 promoter further connected the phospholipid-binding and hormone-related ANXA7 to the major lipidrelevant cell survival cascade and AR signaling in prostate carcinogenesis, consistent with suggested coregulation of ANXA7 and lipoxygenases (Torosyan et al, 2006). Thus, this study provides mechanistic insights into the hnRNP-associated ANXA7 control that can hinder ANXA7 cell survival regulation.…”

“…Unlike the C-terminal with conserved annexin repeats, the unique ANXA7 N-terminal is flanked by the upstream sequences harboring an entirely different set of cis-acting and enhancer elements compared with other annexins (Shirvan et al, 1994). In our study on ANXA7 versus p53 effects on prostate cancer cells (Torosyan et al, 2006), we suggested that ANXA7 can be co-regulated by ribonucleoprotein (heterogeneous nuclear ribonucleoprotein (hnRNP)) K.…”

“…DNA affinity/purification of nuclear proteins followed by mass spectrometry The DNA affinity/enrichment/purification of proteins from PrEC and PC3 nuclear extracts was performed according to the protocols modified by A Dobi, as previously described (Torosyan et al, 2006). The specific probe corresponding to the F-segment (À1086/À890) of ANXA7 promoter was synthesized as double-stranded DNA with biotinylation (Gene Probe Technologies, Gaithersburg, MD, USA).…”

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…It is of note that 21 tumour-suppressor genes map within either the specific or the consistently altered regions. TIMP3 and PTEN have already been reported as tumour suppressors in thyroid tumours (Hu et al, 2006;Hou et al, 2007;Wang et al, 2007), while others are involved in a variety of different tumour types, for example, TGFBR3 and ANXA7 in prostate cancer (Torosyan et al, 2006;Dong et al, 2007), TNFSF15 and TUSC1 in lung cancer (Shan et al, 2004;Hou et al, 2005), SYK and Net1 in breast cancer (Repana et al, 2006;Huang et al, 2007), SLIT1, RSU1 and KLF6 in gliomas and glioblastosmas (Chunduru et al, 2002;Dickinson et al, 2004;Camacho-Vanegas et al, 2007), DBC1 in bladder cancer (Louhelainen et al, 2006), DEC1 in oesophageal squamous cell carcinomas (Yang et al, 2005), RB1 in retinoblastoma (Corson and Gallie, 2007) and LATS2 and DLEU7 in leukaemias (Hammarsund et al, 2004;Jimenez-Velasco et al, 2005). Some of these tumour suppressors have influence on the regulation of chromatin acetylation …”

11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

“…5-LOX increases in human colorectal tumors, and inhibition of the 5-LOX pathway suppresses the proliferation of human colon carcinoma cell lines and inhibits CRC development [56][57][58][59][60]. Dexamethasone has been reported to inhibit 5-LOX expression and its metabolite production [61,62].…”