Secretory phospholipase A2‐IIa is a target gene of the HER/HER2‐elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer

Oleksowicz, Leslie; Liu, Yin; Bracken, R. Bruce; Gaitonde, Krishnanath; Burke, Barbara; Succop, Paul; Levin, Linda; Dong, Zhongyun; Lu, Shan

doi:10.1002/pros.22463

Cited by 34 publications

(27 citation statements)

References 38 publications

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“…Elevated HER/HER2-Vav3-PI3K-Akt-NF-κB signaling induced sPLA2-IIa overexpression and secretion in prostate cancer cells (20,25). However, the underlying role of sPLA2-IIa in cancer development and progression is not known.…”

Section: Discussionmentioning

confidence: 99%

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

Dong

Meller

Succop

et al. 2014

International Journal of Oncology

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Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2-IIa. sPLA2-IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2-PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose-dependent manner in lung cancer cells. The structure and sequence-based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2-IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2-IIa is a potential therapeutic target against lung cancer.

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Section: Discussionmentioning

confidence: 99%

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

Dong

Meller

Succop

et al. 2014

International Journal of Oncology

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“…Studies aimed at blockade of TNF in vivo appear warranted in an effort to determine the relative importance of this cytokine over other factors such as stimulators of the HER/HER2 pathway [64] that may activate eicosanoid-related growth stimulatory pathways in PCa.…”

Section: Potential Role Of Tnf In Eicosanoid Pathways In Pcamentioning

confidence: 99%

Paradoxical Roles of Tumour Necrosis Factor-Alpha in Prostate Cancer Biology

2012

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Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications.

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“…PLA2G2A mRNA is upregulated in lung and prostate cancer cells (Oleksowicz et al 2012;Yu et al 2012a). Furthermore, reducing expression of PLA2G2A by hairpin RNA reduces the proliferation of lung cancer cells, consistent with an oncogenic role for PLA2G2A (Yu et al 2012b).…”

Section: Discussionmentioning

confidence: 68%

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

et al. 2014

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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.

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Secretory phospholipase A2‐IIa is a target gene of the HER/HER2‐elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer

Cited by 34 publications

References 38 publications

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

Paradoxical Roles of Tumour Necrosis Factor-Alpha in Prostate Cancer Biology

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

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