Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Ronca, Roberto; Giacomini, Arianna; Salle, Emanuela Di; Coltrini, Daniela; Pagano, Katiuscia; Ragona, Laura; Matarazzo, Sara; Rezzola, Sara; Maiolo, Daniele; Torella, Rubben; Moroni, Elisabetta; Mazzieri, Roberta; Escobar, Giulia; Mor, Marco; Colombo, Giorgio; Presta, Marco

doi:10.1016/j.ccell.2015.07.002

Cited by 101 publications

(130 citation statements)

References 40 publications

(58 reference statements)

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“…Studies have revealed that PTX3 directly alter the cell survival pathways or facilitating tumor-stromal interactions in GEM resistance of pancreatic cancer cells (Kondo et al, 2013). Our study findings provided an additional support for the The expression of PTX3 is high in most lung cancers and preinvasive neoplastic lesions, suggesting its role in the pathogenesis and progression of lung neoplasia (Ronca et al, 2015;Rusnati et al, 2004). At the common sites of metastasis, tumor-associated stromal cells produce a high quantity of PTX3 thus indicating an important role of Akt/ERK signaling in lung cancer progression and metastasis (Chang et al, 2015).…”

Section: Discussionsupporting

confidence: 75%

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Ahmmed

Kampo

Khan

et al. 2019

Journal Cellular Physiology

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PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM‐induced production of ROS‐mediated activation of Akt and extracellular signal‐regulated kinase (ERK) pathways and inhibits nuclear piling‐up of nuclear factor kappa B (NF‐κB) and HIF‐1α. On the basis of time and dose‐dependent manner, our data demonstrated that GEM‐induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N‐acetyl‐l‐cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time‐dependent escalation of NF‐κB and HIF‐1α in the nucleus resulted from phosphorylation‐induced degradation of IκBα, whereas HIF‐1α upregulation was NF‐κB‐dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF‐κB and HIF‐1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF‐κB and HIF‐1α and their pharmacological inhibition suppressed GEM‐induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM‐induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF‐κB downregulation in lung cancer.

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Section: Discussionsupporting

confidence: 75%

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Ahmmed

Kampo

Khan

et al. 2019

Journal Cellular Physiology

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“…In this scheme, PTX3 was found to bind certain members of the fibroblast growth factor (FGF) family (in particular FGF2 and FGF8b), suppressing FGF-induced neovascularization and hampering tumor formation in xenograft models (52, 53). Similarly, PTX3 was shown to exert antimetastatic effects in melanoma (54) and to act as an extrinsic factor that inhibits cancer growth in a variety of additional heterotypic, syngeneic, and autochthonous prostate, lung, and pancreatic tumor models (55). These notions were further reinforced by Bonavita et al (56), who showed that PTX3 ablation sensitized animals to carcinogen-induced tumorigenesis through the creation of a favorable immune tumor microenvironment that in turn stimulated oxidative stress and genetic instability in the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Pentraxin-3 is a PI3K signaling target that promotes stem cell–like traits in basal-like breast cancers

et al. 2017

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Basal-like breast cancers (BLBCs) exhibit hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway because of the frequent mutational activation of the PIK3CA catalytic subunit and the genetic loss of its negative regulators PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate-4-phosphatase type II). However, PI3K inhibitors have had limited clinical efficacy in BLBC management because of compensatory amplification of PI3K downstream signaling loops. Therefore, identification of critical PI3K mediators is paramount to the development of effective BLBC therapeutics. Using transcriptomic analysis of activated PIK3CA–expressing BLBC cells, we identified the gene encoding the humoral pattern recognition molecule pentraxin-3 (PTX3) as a critical target of oncogenic PI3K signaling. We found that PTX3 abundance is stimulated, in part, through AKT- and nuclear factor κB (NF-κB)–dependent pathways and that presence of PTX3 is necessary for PI3K-induced stem cell–like traits. We further showed that PTX3 expression is greater in tumor samples from patients with BLBC and that it is prognostic of poor patient survival. Our results thus reveal PTX3 as a newly identified PI3K-regulated biomarker and a potential therapeutic target in BLBC.

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“…123 In mouse TRAMP-C2 prostate cancer and B16 melanoma models, PTX3 overexpression results in a reduced FGF-dependent tumor growth, melanoma metastasis and cancer-associated angiogenesis. 160 However, in head and neck tumors, PTX3 appears to promote tumor cell migration and invasion, while in gliomas tumor cell proliferation. 161,162 In gastric cancer, PTX3 expression is associated with the extent of tumor cell invasion, and PTX3 gene silencing results in a reduced cancer-related inflammation.…”

Section: Ptx3 In the Response To Tissue Damage And Repairmentioning

confidence: 99%

The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis

Erreni

Manfredi

Garlanda

et al. 2017

Immunological Reviews

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Tissue damage frequently occurs. The immune system senses it and enforces homeostatic responses that lead to regeneration and repair. The synthesis of acute phase molecules is emerging as a crucial event in this program. The prototypic long pentraxin PTX3 orchestrates the recruitment of leukocytes, stabilizes the provisional matrix in order to facilitate leukocyte and stem progenitor cells trafficking, promotes swift and safe clearance of dying cells and of autoantigens, limiting autoimmunity and protecting the vasculature. These non-redundant actions of PTX3 are necessary for the resolution of inflammation. Recent studies have highlighted the mechanisms by which PTX3 adapts the functions of innate immune cells, orchestrates tissue repair and contributes to select the appropriate acquired immune response in various tissues. Conversely, PTX3 continues to be produced in diseases where the inflammatory response does not resolve. It is therefore a valuable biomarker for more precise and personalized stratification of patients, often independently predicting clinical evolution and outcome. There is strong promise for novel therapies based on understanding the mechanisms with which PTX3 plays its homeostatic role, especially in regulating leukocyte migration and the resolution of inflammatory processes.

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Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Cited by 101 publications

References 40 publications

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Pentraxin-3 is a PI3K signaling target that promotes stem cell–like traits in basal-like breast cancers

The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis

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