Oncogenic action of phospholipase A2 in prostate cancer

Dong, Qihan; Patel, Manish I.; Scott, Kieran F.; Graham, Garry G.; Russell, Pamela J.; Sved, Paul

doi:10.1016/j.canlet.2005.08.012

Cited by 93 publications

(70 citation statements)

References 53 publications

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“…In fact, several studies evidenced that PLA2 activity is modulated by both agonists and antagonists of steroid hormones (e.g., 17b-estradiol, progesterone, and tamoxifen), in breast as well as in other tissues [45][46][47][48]. Another possible mechanism may be related to the significant expression of Annexin II (an endogeneous inhibitor of PLA2 activity) in breast cancer tissues respect to the undetectable levels in normal and hyperplastic breast ductal epithelial cells [49]; the dysregulated balance between sPLA2-IIa activity and its inhibition by annexins has been proposed in the pathogenesis of prostate cancer [50]. Further studies are in progress to evaluate the presence and age-dependent expression of annexins in NAF collected from healthy and cancer patients to explain the age-dependence of sPLA2-IIa down-regulation.…”

Section: Discussionmentioning

confidence: 99%

Nipple aspirate fluids from women with breast cancer contain increased levels of group IIa secretory phospholipase A2

Mannello

Qin

Zhu

et al. 2007

Breast Cancer Res Treat

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Arachidonic acid, a bioactive molecule metabolized into prostaglandins and leukotrienes, contributes to cellular proliferation and tumor progression. Group IIa secretory phospholipase A2 (sPLA2-IIa) can facilitate arachidonate release from cellular phospholipids, suggesting its involvement in tumor evolution. Analysis of breast nipple aspirate fluid (NAF), a noninvasive research tool, allows the identification of biomarkers of breast cancer. We sought to determine whether sPLA2-IIa expression might be related to breast cancer development or progression. sPLA2-IIa expression was evaluated in NAF samples from 110 women (57 women with and 53 without breast cancer) using ELISA and western blotting; ultrastructural immunolocalization was performed in epithelial cells floating in NAF. Immunocytochemistry revealed that sPLA2-IIa is a constitutive intracellular protein suggesting that breast ductal cells synthesize and secrete the 14 kDa protein in NAF. Among all 110 subjects, sPLA2-IIa expression was significantly increased both in NAF and within ductal epithelial cells from cancer containing breasts. While in healthy women menopausal status did not influence sPLA2-IIa expression (P = 0.457), among patients with breast cancer there was a significant down-regulation in postmenopausal subjects (P < 0.0001). Moreover, sPLA2-IIa concentration in NAF from breast cancer patients was positively correlated with tumor stage (r (2) = 0.979, P = 0.0012), suggesting an active secretion/accumulation of the enzyme in NAF based on tumor burden. sPLA2-IIa activity may serve a dual role in breast carcinogenesis, beneficial in its release of arachidonate and detrimental in the metabolic conversion of arachadonic acid into prostaglandins and leukotrienes.

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Section: Discussionmentioning

confidence: 99%

Nipple aspirate fluids from women with breast cancer contain increased levels of group IIa secretory phospholipase A2

Mannello

Qin

Zhu

et al. 2007

Breast Cancer Res Treat

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“…The production of arachidonic acid occurs mainly by activation of PL2A in response to different extracellular stimuli. Expression of PL2A was increased in several cancers, and it became as target for anticancer drugs [16].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of CD24, c-myc and Phospholipase 2A in Prostate Cancer Tissue Samples Obtained by Needle Biopsy

Nagy

Szendrői

Romics

2008

Pathol. Oncol. Res.

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Altered CD24, c-myc and phospholipase 2a expression was reported in different cancers. Our aim was to measure the expression of these genes in prostate cancer tissues, and compare it to non-cancerous samples. Prostate tissue samples were collected by needle biopsy from 20 prostate cancer (PCA) and 11 benign prostate hyperplasic (BPH) patients. RNA was isolated; cDNA synthetized, CD24, c-myc and phospholipase 2A (PL2A) expressions were determined by quantitative real-time PCR method. The expression of beta-globin gene was measured for normalization of the gene expression results. Serum prostate specific antigen (PSA) levels were determined by microparticle enzyme immunoassay (MEIA) method. PSA levels were significantly different between the PCA and BPH groups, 252.37 +/- 308.33 ng/ml vs. 3.5 +/- 2.14 ng/ml (p = 0.001), respectively. CD24 expression was 988.86 +/- 3041 ng/microl in prostate tumor and 4.00 +/- 4.25 ng/microl in the BPH group (p = 0.035). The c-myc expression was 88.32 +/- 11.93 ng/microl in the prostate tumor and 17.08 +/- 21.75 ng/microl in the BPH group (p = 0.02), and the PL2A 31.36 +/- 67.02 ng/microl was in PCA and 5.56 +/- 14.08 ng/microl in BPH (p = 0.025). Gleason's scores showed correlation with c-myc (p = 0.019) and PSA (p = 0.033) levels. Overexpression of PL2A, CD24 and c-myc was observed in prostate cancer samples using quantitative real-time PCR method.

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“…Additionally, arachidonic acid is stored in cell membranes and is made available by phospholipases under conditions of increased inflammatory response (32). Arachidonic acid is further metabolized by cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 monooxygenases to yield bioactive products that have myriad effects on cells, and altered metabolism of arachidonic acid by COX, LOX, and P450 has been implicated in cancer progression (31,(33)(34)(35)(36).We have studied mechanisms of cell adhesion using the MDA-MB-435 cells as a model of a highly metastatic human * This work was supported, in whole or in part, by the National Institutes of …”

mentioning

confidence: 99%

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression of these proteins have been observed in human cancers and have been implicated as important factors in metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such as type IV collagen. Here we report that in MDA-MB-435 human melanoma cells, arachidonic acid activates RhoA, and inhibition of RhoA signaling with either C3 exoenzyme or dominant negative Rho blocked arachidonic acid-induced cell adhesion. Inhibition of the Rho kinase (ROCK) with either small molecule inhibitors or ROCK II-specific small interfering RNA (siRNA) blocked the fatty acid-induced adhesion. However, unlike other systems, inhibition of ROCK did not block the activation of p38 mitogenactivated protein kinase (MAPK); instead, Rho activation depended on p38 MAPK activity and the presence of heat shock protein 27 (HSP27), which is phosphorylated downstream of p38 after arachidonic acid treatment. HSP27 associated with p115RhoGEF in fatty acid-treated cells, and this association was blocked when p38 was inhibited. Furthermore, siRNA knockdown of HSP27 blocked the fatty acid-stimulated Rho activity. Expression of dominant negative p115-RhoGEF or p115RhoGEF-specific siRNA inhibited both RhoA activation and adhesion on type IV collagen, whereas a constitutively active p115RhoGEF restored the arachidonic acid stimulation in cells in which the p38 MAPK had been inhibited. These data suggest that n-6 dietary fatty acids stimulate a set of interactions that regulates cell adhesion through RhoA and ROCK II via a p38 MAPK-dependent association of HSP27 and p115RhoGEF.The ability of tumor cells to metastasize to secondary sites is a hallmark of neoplastic disease. Unfortunately, this propensity to spread is the primary cause of morbidity and death in cancer patients (1). Metastasis is clearly a highly regulated, multistep process that occurs in a spatiotemporal manner (2-4). To escape the restrictive compartment boundaries characteristic of adult tissue, separate intravasation and extravasation steps requiring alterations in co-adhesion, adhesion, invasion, and migration must occur. Execution of these biological processes, involving multiple proteins and cellular organelles, require highly coordinated cell signaling mechanisms.The Rho family of small GTPases regulates many facets of cytoskeletal rearrangements that facilitate cell attachment and migration (5-7). Rho GTPases act as molecular switches by changing from an inactive GDP-bound conformation to an active GTPbound conformation, thereby regulating a signaling pathway. These proteins are directly regulated by Rho guanine nucleotide exchange factors (GEFs), 2 Rho GTPase activating proteins, and Rho GDP-dissociation inhibitors (8 -12). RhoGEFs bind to the GTPase to catalyze the dissociation of GDP, allowing the binding of GTP and thereby promoting Rho activation (8). The RGS (regulators of G protein signaling) domain-c...

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Oncogenic action of phospholipase A2 in prostate cancer

Cited by 93 publications

References 53 publications

Nipple aspirate fluids from women with breast cancer contain increased levels of group IIa secretory phospholipase A2

Nipple aspirate fluids from women with breast cancer contain increased levels of group IIa secretory phospholipase A2

Overexpression of CD24, c-myc and Phospholipase 2A in Prostate Cancer Tissue Samples Obtained by Needle Biopsy

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

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