PTEN and PHLPP crosstalk in cancer cells and in TGFβ-activated stem cells

Ghalali, Aram; Ye, Zhiwei; Högberg, Johan; Stenius, Ulla

doi:10.1016/j.biopha.2020.110112

Cited by 10 publications

(13 citation statements)

References 64 publications

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“…This could be because inhibiting P2X4R alone is not sufficient enough to affect PCa apoptosis, as has been shown for breast cancer, where P2X4R modulates cell death via coordinating with other receptors/signalling such as the P2X7R and Pannexin-1 channel [40]. Furthermore, consistent with findings by Ghalali et al [25], our migration and invasion data demonstrates that inhibiting P2X4R impairs the mobility of PCa cells. All these results suggest that P2X4R plays a comprehensive role in multiple aspects of PCa biology, which warrants further studies to reveal the molecular and cellular mechanisms involved.…”

Section: Discussionsupporting

confidence: 88%

“…Limited evidence showed that the antidepressant paroxetine, a P2X4R inhibitor, induced [Ca 2+ ] i rises in human PCa cells [23], indicating a functional role of P2X4R in PCa progression [24]. More recently, P2X4R was shown to be involved in TGFβ-1 induced invasiveness and epithelial-to-mesenchymal transition (EMT) in PCa cells [25]. These studies suggested a complex link between P2X4R and PCa activities.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

Zhou

Carrera

et al. 2020

Cells

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men, causing considerable morbidity and mortality. The P2X4 receptor (P2X4R) is the most ubiquitously expressed P2X receptor in mammals and is positively associated with tumorigenesis in many cancer types. However, its involvement in PCa progression is less understood. We hypothesized that P2X4R activity enhanced tumour formation by PCa cells. We showed that P2X4R was the most highly expressed, functional P2 receptor in these cells using quantitative reverse transcription PCR (RT-PCR) and a calcium influx assay. The effect of inhibiting P2X4R on PCa (PC3 and C4-2B4 cells) viability, proliferation, migration, invasion, and apoptosis were examined using the selective P2XR4 antagonists 5-BDBD and PSB-12062. The results demonstrated that inhibiting P2X4R impaired the growth and mobility of PCa cells but not apoptosis. In BALB/c immunocompromised nude mice inoculated with human PC3 cells subcutaneously, 5-BDBD showed anti-tumourigenic effects. Finally, a retrospective analysis of P2RX4 expression in clinical datasets (GDS1439, GDS1746, and GDS3289) suggested that P2X4R was positively associated with PCa malignancy. These studies suggest that P2X4R has a role in enhancing PCa tumour formation and is a clinically targetable candidate for which inhibitors are already available and have the potential to suppress disease progression.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

Zhou

Carrera

et al. 2020

Cells

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“…IL-1b has also been shown to be up-regulated in the epidermis after challenge with a sensitizer in a mouse model (Shornick et al 2001). Traditionally, inflammasome activation has mainly been studied in immune cells, but it is now known to be activated also in airway epithelia (Zheng et al 2017;Brostrom et al 2018;Ghalali et al 2020) and keratinocytes (Galbiati et al 2019). Inflammasome activation (Koppes et al 2017) and IL-1b secretion (Kaplan et al 2012) can be initiated by toxicological stress in epithelial cells which release danger-associated molecular patterns (DAMP), such as ATP or/and autotaxin (ATX), and affect neighboring cells (Zheng et al 2017;Brostrom et al 2018;Ghalali et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Impact of mono-culture vs. Co-culture of keratinocytes and monocytes on cytokine responses induced by important skin sensitizers

Karri

Lidén

Fyhrquist

et al. 2021

Journal of Immunotoxicology

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Sensitization to a contact allergen brings with it a lifelong risk to develop allergic contact dermatitis. Inflammation is an important part of the skin sensitizing mechanism, and understanding how different haptens stimulate the immune system, as well as the role played by different cell types present in skin, may be helpful for developing optimized in vitro models for risk assessment of new chemicals or mixtures. The aim of this study was to compare the cytokine profile following exposure of cells representing keratinocytes (HaCaT), monocytes (THP-1) and a co-culture of these cells to three clinically important skin sensitizers: cobalt (II) chloride (CoCl 2 ), methylisothiazolinone (MI) and p-phenylenediamine (PPD). Secretion of ten pro-inflammatory cytokines was measured using multiplexing. The results showed that the cytokine response differed substantially between the three cell assays. CoCl 2 caused an increase of IL-8 in HaCaT cells, while the induction of also IL-13 and IL-1b was observed in THP-1 cells and co-cultures. MI induced six cytokines in HaCaT cells but only IL-1b in the THP-1 cells and four cytokines in the co-culture. Interestingly, the IL-1b response was massive in the co-culture. PPD caused release of IL-1b in all three models as well as IL-8 in the co-culture. Control experiments with two non-sensitizers and irritants (lactic acid and sodium dodecyl sulfate) showed no effect on IL-8 or IL-1b in the co-culture. Taken together, results from this exploratory analysis show unique cytokine profiles dependent on the type of hapten and cell model. Importantly, all three haptens triggered secretion of IL-1b and IL-8 in a co-culture of HaCaT cells and THP-1 cells, representing the most robust test system.

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“…Additionally, the biological associations of P2X4 receptors and PTEN is not yet fully investigated. PTEN is a negative regulator of PI3K resulting in de-phosphorylation of Akt (62). Phosphorylated Akt (p-Akt), its active form, is associated with poor prognosis in multiple cancers and promotes mesenchymal-like properties and metastasis of PCa cells (63).…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated Akt (p-Akt), its active form, is associated with poor prognosis in multiple cancers and promotes mesenchymal-like properties and metastasis of PCa cells (63). Interestingly, a study reported crosstalk between PTEN and another Akt regulatory phosphatase, PHLPP that is dependent on P2X4 receptor signaling (62). The authors propose that this crosstalk controls the levels of p-Akt, promotes PCa cell invasion, and is mediated by the P2X4 purinergic receptor.…”

Section: Discussionmentioning

confidence: 99%

P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

Vidal

et al. 2021

Preprint

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Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. Herein, we report that the P2X4 purinergic receptor is overexpressed in PCa, associated with PCa metastasis, and a driver of tumor development in vivo. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer compared to benign tissue spots, in prostatic intraepithelial neoplasia, in cancer from White compared to Black men, and in PCa with ERG positivity or with PTEN loss. High P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with P2X4-specific agonist CTP increased transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. P2X4 antagonist 5-BDBD treatment resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identifies P2X4 as a candidate for therapeutic targeting.

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PTEN and PHLPP crosstalk in cancer cells and in TGFβ-activated stem cells

Cited by 10 publications

References 64 publications

Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

Impact of mono-culture vs. Co-culture of keratinocytes and monocytes on cytokine responses induced by important skin sensitizers

P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

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