Expression of secretory phospholipase A2 in colon tumor cells potentiates tumor growth

Belinsky, Glenn S.; Rajan, T. V.; Saria, Elizabeth A.; Giardina, Charles; Rosenberg, Daniel W.

doi:10.1002/mc.20271

Cited by 44 publications

(34 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Currently, the major known functions of PLA2G2A are largely related to inflammatory responses, antimicrobial defense, and phospholipid degradation in the gastrointestinal track (6). Furthermore, although PLA2G2A has been proposed as a potential tumor suppressor, evidence supporting this model is conflicting (5,(7)(8)(9)(10). Clarifying the functional relationship between PLA2G2A and GC will thus require (a) characterizing the cellular pathways regulating PLA2G2A, (b) testing if PLA2G2A functionally contributes or is merely associated with improved patient survival, and (c) identifying PLA2G2A downstream target genes that might mediate its prosurvival effect.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Ganesan¹,

Ivanova²,

Wu³

et al. 2008

Cancer Research

107

View full text Add to dashboard Cite

Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. To elucidate function and regulation of PLA2G2A in GC, we analyzed a panel of GC cell lines. PLA2G2A was specifically expressed in lines with constitutive Wnt activity, implicating B-catenin-dependent Wnt signaling as a major upstream regulator of PLA2G2A expression. The invasive ability of PLA2G2A-expressing AGS cells was enhanced by PLA2G2A silencing, whereas cellular migration in non-PLA2G2A -expressing N87 cells was inhibited by enforced PLA2G2A expression, indicating that PLA2G2A is both necessary and sufficient to function as an inhibitor of GC invasion in vitro. We provide evidence that antiinvasive effect of PLA2G2A occurs, at least in part, through its ability to inhibit the S100A4 metastasis mediator gene. Consistent with its invasion inhibitor role, PLA2G2A expression was elevated in primary gastric, colon, and prostrate early-stage tumors, but was decreased in metastatic and late-stage tumors. There was a strong association between PLA2G2A promoter methylation status and PLA2G2A expression, suggesting that the loss of PLA2G2A expression in late-stage cancers may be due to epigenetic silencing. Supporting this, among the non-PLA2G2A-expressing lines, pharmacologic inhibition of epigenetic silencing reactivated PLA2G2A in Wnt-active lines, but in non-Wnt-active lines, a combination of Wnt hyperactivation and inhibition of epigenetic silencing were both required for PLA2G2A reactivation. Our results highlight the complexity of PLA2G2A regulation and provide functional evidence for PLA2G2A as an important regulator of invasion and metastasis in GC.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Ganesan¹,

Ivanova²,

Wu³

et al. 2008

Cancer Research

107

View full text Add to dashboard Cite

show abstract

“…In vitro, group IB, IIA, and III sPLA 2 s have been reported to stimulate cell proliferation and activation of MAP kinases in various cancer cells (Kinoshita et al, 1997;Sved et al, 2004;Murakami et al, 2005). Finally, subcutaneous injection into nude mice of colon tumor cells overexpressing mGIIA sPLA 2 resulted in a 2.5-fold increase in tumor size (Belinsky et al, 2007).…”

mentioning

confidence: 97%

Group X Phospholipase A₂ Stimulates the Proliferation of Colon Cancer Cells by Producing Various Lipid Mediators

Surrel¹,

Jemel²,

Boilard³

et al. 2009

Mol Pharmacol

View full text Add to dashboard Cite

Among mammalian secreted phospholipases A 2 (sPLA 2 s), the group X enzyme has the most potent hydrolyzing capacity toward phosphatidylcholine, the major phospholipid of cell membrane and lipoproteins. This enzyme has recently been implicated in chronic inflammatory diseases such as atherosclerosis and asthma and may also play a role in colon tumorigenesis. We show here that group X sPLA 2 [mouse (m)GX] is one of the most highly expressed PLA 2 in the mouse colon and that recombinant mouse and human enzymes stimulate proliferation and mitogen-activated protein kinase activation of various colon cell lines, including Colon-26 cancer cells. Among various recombinant sPLA 2 s, mGX is the most potent enzyme to stimulate cell proliferation. Based on the use of sPLA 2 inhibitors, catalytic site mutants, and small interfering RNA silencing of cytosolic PLA 2 ␣ and M-type sPLA 2 receptor, we demonstrate that mGX promotes cell proliferation independently of the receptor and via its intrinsic catalytic activity and production of free arachidonic acid and lysophospholipids, which are mitogenic by themselves. mGX can also elicit the production of large amounts of prostaglandin E 2 and other eicosanoids from Colon-26 cells, but these lipid mediators do not play a role in mGX-induced cell proliferation because inhibitors of cyclooxygenases and lipoxygenases do not prevent sPLA 2 mitogenic effects. Together, our results indicate that group X sPLA 2 may play an important role in colon tumorigenesis by promoting cancer cell proliferation and releasing various lipid mediators involved in other key events in cancer progression.Phospholipases A 2 (PLA 2 s) catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids to generate free fatty acids and lysophospholipids (Schaloske and Dennis, 2006;Lambeau and Gelb, 2008). Over the past few years, it has been realized that PLA 2 s constitute a superfamily of enzymes comprising several intracellular enzymes and secreted PLA 2 s (sPLA 2 s).The group IVA cytosolic PLA 2 (cPLA 2 ␣) is the best known intracellular PLA 2 , and it clearly plays an important, yet not exclusive role in the release of arachidonic acid (AA) and subsequent production of eicosanoids in various biological settings (Kita et al., 2006). In contrast, the biological functions of the different sPLA 2 s are slowly being unraveled. sPLA 2 s have been implicated in lipid digestion and obesity; activation of immune cells; asthma; atherosclerosis; acute respiratory distress syndrome; and host defense against bac-

show abstract

“…Our orthotopic xenograft study clearly demonstrates a non-cell-autonomous role for Pla2g2a. HCT116 human colon cancer cells express little endogenous Pla2g2a (Belinsky et al 2007), yet we found that their growth in the cecal wall of nude mice was affected in a manner that correlated with the level of cecal Pla2g2a transcript ( Figure 3D). The number of polyps that develop when fetal small intestinal tissues from Apc Min mice were grafted subcutaneously was previously shown to correlate with the Mom-1 allele status (sensitive or resistant) of the isograft's donor rather than of the host mouse (Gould and Dove 1996).…”

Section: Discussionmentioning

confidence: 86%

“…It was previously reported that overexpression of mouse Pla2g2a in HCT116 cells increased xenograft tumor size when these colon cancer cells were implanted subcutaneously in nude mice (Belinsky et al 2007). This seemingly contradictory result might be explained by differences in the cell expressing Pla2g2a (implanted human cancer cells vs. surrounding mouse tissues) or the site of the xenograft implantation (subcutaneous vs. cecal wall).…”

Section: Discussionmentioning

confidence: 93%

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

et al. 2014

View full text Add to dashboard Cite

Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies.

show abstract

Expression of secretory phospholipase A2 in colon tumor cells potentiates tumor growth

Cited by 44 publications

References 45 publications

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Group X Phospholipase A₂ Stimulates the Proliferation of Colon Cancer Cells by Producing Various Lipid Mediators

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Contact Info

Product

Resources

About

Expression of secretory phospholipase A2 in colon tumor cells potentiates tumor growth

Cited by 44 publications

References 45 publications

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Group X Phospholipase A2 Stimulates the Proliferation of Colon Cancer Cells by Producing Various Lipid Mediators

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Contact Info

Product

Resources

About

Group X Phospholipase A₂ Stimulates the Proliferation of Colon Cancer Cells by Producing Various Lipid Mediators