Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Patel, Rachana; Gao, Meiling; Ahmad, Imran; Fleming, Janis; Singh, Lukram Babloo; Singh, Taranjit; McKie, Arthur B.; Seywright, Morag; Barnetson, Robert J.; Edwards, Joanne; Sansom, Owen J.; Leung, Hing Y.

doi:10.1172/jci63672

Cited by 81 publications

(99 citation statements)

References 42 publications

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“…Moreover, our results show that the positive staining signals of phosphorylated PTEN in CCA group were seen in the cytoplasm as well as in the nucleus of tumor cells. This may be due to the effect of phosphorylation of PTEN at Ser380/Threo382/ Threo383 which may promote nuclear accumulation (Patel et al, 2013). Moreover the expression of phosphorylated PTEN has been detected in many cancers, such as lung cancer (David, 2001), prostate cancer (Koumakpayi et al, 2010;Patel et al, 2013), and glioblastoma (Fenton et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…This may be due to the effect of phosphorylation of PTEN at Ser380/Threo382/ Threo383 which may promote nuclear accumulation (Patel et al, 2013). Moreover the expression of phosphorylated PTEN has been detected in many cancers, such as lung cancer (David, 2001), prostate cancer (Koumakpayi et al, 2010;Patel et al, 2013), and glioblastoma (Fenton et al, 2012). Therefore, our results suggest that PTEN inactivation by phosphorylation is responsible for PI3K/ AKT activation during CCA carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Yothaisong¹,

Thanee²,

Namwat³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and Wnt/β-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/ AKT/PTEN and Wnt/β-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the p85α-regulatory and p110α-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of Wnt/β-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and β-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of β-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Yothaisong¹,

Thanee²,

Namwat³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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“…These data are in agreement with two recent reports showing that deletion of Spry family members in the context of Pten happloinsuficiency accelerates prostate tumorigenesis. 51,52 During the last years, it is becoming evident that OIS poses a potent barrier to tumoral transformation in vivo. Thus, the expression of activated Ras, E2f3 or B-Raf oncogenes in mice induces cellular senescence in premalignant tumors of the lung, pancreas, mammary gland, pituitary gland and melanoma.…”

Section: Discussionmentioning

confidence: 99%

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...

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“…Recent studies have pointed out the significant role of sprouty2, a substrate of Mnk1, during multiple diseases or physiological process such as human mesenchymal stem cell differentiation, 17 papillary thyroid cancer, 18 and prostate cancer progression 19 by regulating ERK signaling pathway. ERK1/2 is one of the most important signaling that could provide new treatment strategies for cardiac hypertrophy and remodeling.…”

Section: Discussionmentioning

confidence: 99%

Mnk1 (Mitogen-Activated Protein Kinase–Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice

Yuan

Ling

et al. 2016

Hypertension

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Identifying the key factor involved in cardiac remodeling is critically important for developing novel strategies to protect against heart failure. Here, the role of Mnk1 (mitogen-activated protein kinase–interacting kinase 1) in cardiac remodeling was clarified. Cardiac remodeling was induced by transverse aortic constriction in Mnk1-knockout mice and their wild-type control mice. After 4 weeks of transverse aortic constriction, Mnk1-knockout mice developed exaggerated cardiac hypertrophy, fibrosis, dysfunction, and cardiomyocyte apoptosis and showed increased ERK1/2 (extracellular signal–regulated kinase 1/2) activation along with reduced sprouty2 expression. In line with the in vivo studies, Mnk1 knockdown by Mnk1 siRNA transfection induced exaggerated angiotensin II–induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs). Moreover, adenovirus-mediated overexpression of Mnk1 in NRVMs protected cardiomyocytes from angiotensin II–induced hypertrophy. In addition, overexpression of sprouty2 rescued NRVMs with Mnk1 knockdown from angiotensin II–induced hypertrophy. In accordance with the in vivo studies, as compared with the control group, Mnk1 knockdown led to hyperphosphorylation of ERK1/2 and suppression of the sprouty2 expression in angiotensin II–treated NRVMs; furthermore, Mnk1 overexpression led to hypophosphorylation of ERK1/2 in angiotensin II–treated NRVMs. In addition, sprouty2 overexpression suppressed the activation of ERK1/2 in angiotensin II–treated NRVMs with Mnk1 knockdown. Impressively, MnK1-knockout mice with overexpression of sprouty2 exhibited signs of a blunted cardiac hypertrophic response. Mnk1 likely carries out a suppressive function in cardiac hypertrophy via regulating the sprouty2/ERK1/2 pathway. It implicates Mnk1 in the development of cardiac remodeling.

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Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Cited by 81 publications

References 42 publications

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Mnk1 (Mitogen-Activated Protein Kinase–Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice

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