PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers

Labbé, David P.; Uetani, Noriko; Vinette, Valérie; Lessard, Laurent; Aubry, Isabelle; Migon, Eva; Sirois, Jacinthe; Haigh, Jody J.; Bégin, Louis R.; Trotman, Lloyd C.; Paquet, Marilène; Tremblay, Michel L.

doi:10.1158/0008-5472.can-15-1501

Cited by 19 publications

(18 citation statements)

References 18 publications

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“…The mechanism of HFDinduced tumor progression of prostate cancer may not only be inflammation. Changes in cholesterol in the cell membrane or a deficiency of the protein tyrosine phosphatase 1B with administration of an HFD might result in tumor progression of PTEN-deficient prostate cancer (43,44).…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Hayashi

Fujita

Nojima

et al. 2018

Clinical Cancer Research

122

107

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High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre;(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed. HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer. HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. .

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Section: Discussionmentioning

confidence: 99%

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Hayashi

Fujita

Nojima

et al. 2018

Clinical Cancer Research

122

107

View full text Add to dashboard Cite

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“…Paradoxical effects of PTP1B in tumor progression also occurred in different prostate cancer animal models. PTP1B has been linked with a tumorpromoting function for migration and invasion in prostate cancer, which is dependent on androgen receptor signaling (Lessard et al 2012), whereas coordinated loss of PTP1B in PTEN-deficient mice caused an invasive prostate cancer upon high-fat diet feeding due to elevated PI3K-AKT signaling (Labbe et al 2016). Finally, the PRLs (phosphatase of regenerating liver) offer an intriguing example of a PTP that serves an oncogenic function through a mechanism that does not involve the catalytic activity of the enzyme; instead, it promotes tumor growth by forming a heterodimer with members of the CNNM family of magnesium transporters and regulating levels of intracellular magnesium (Hardy et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

et al. 2017

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Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. () resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of and via CRISPR/CAS9 also attenuated tumor outgrowth from knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of.

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“…PTP1B (DA) expression was achieved by crossing these mice to Meox2-Cre mice. Excision of the STOP cassette was assessed by live imaging as previously described ( Figure S2B) (47). Two weeks post TAC, Flag-PTP1B immunoprecipitation from heart lysates validated PTP1B (DA) expression in Rosa26 PTPN1-DA/WT mice compared to Rosa26 WT/WT control littermates and revealed that AGO2 was a substrate of PTP1B in vivo ( Figure 5B).…”

Section: Ago2 Is a Substrate Of Ptp1b In Cardiomyocytes And In Heartsmentioning

confidence: 89%

Protein Tyrosine Phosphatase 1B Regulates MicroRNA-208b-Argonaute 2 Association and Thyroid Hormone Responsiveness in Cardiac Hypertrophy

Coulis

Shi

Labbé

et al. 2019

Preprint

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Elevated reactive oxygen species (ROS) production plays an important role in the pathogenesis of several diseases, including cardiac hypertrophy. While the regulation of diverse sources of ROS is well characterized in the heart, the redox-sensitive targets that contribute to redox signaling remain largely undefined. We now report that protein tyrosine phosphatase 1B (PTP1B) is reversibly oxidized and inactivated in hearts undergoing hypertrophy and that gene deletion of PTP1B in mouse hearts cause an hypertrophic phenotype that is critically exacerbated in mice subjected to pressure overload. Furthermore, we show that PTP1B dephosphorylates Tyr 393 on argonaute 2, a key component of the RNA-induced silencing complex, and sustains gene silencing in the heart. Our results indicate that PTP1B inactivation and argonaute 2 Tyr 393 phosphorylation specifically prevents argonaute 2 from interacting with miR-208b.Phosphorylation and inactivation of argonaute 2 in PTP1B cKO mice revealed a mechanism by which defective miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1/MED13) contributes to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3), using propylthiouracil, rescued TAC-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity exerts a cardioprotective effect in the heart and that redox signaling is tightly linked to thyroid hormone responsiveness and to microRNA-mediated gene silencing in pathological hypertrophy.

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PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers

Cited by 19 publications

References 18 publications

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Protein Tyrosine Phosphatase 1B Regulates MicroRNA-208b-Argonaute 2 Association and Thyroid Hormone Responsiveness in Cardiac Hypertrophy

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