Stable Suppression of Tumorigenicity by Pin1-Targeted RNA Interference in Prostate Cancer

Ryo, Akihide; Uemura, Hiroji; Ishiguro, Hitoshi; Saitoh, Tatsuya; Yamaguchi, Akira; Perrem, Kilian; Kubota, Yoshinobu; Lu, Kun Ping; Aoki, Ichiro

doi:10.1158/1078-0432.ccr-05-0457

Cited by 103 publications

(93 citation statements)

References 35 publications

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“…Among them, the c-MYC proto-oncogene is found implicated in many tumors, and its overexpression can elicit cell transformation. 30 Unlike the effects seen in prostate cancer cells and in neuronal cells, 8,17,31 we observed an increased number of PIN1 KD T98G GM cells in G1 without a parallel increase in apoptotic or senescent cells, suggesting a cell-specific function of Pin1 in different pathways that control the equilibrium between growth, survival, and death.…”

Section: Discussioncontrasting

confidence: 54%

“…Moreover, loss of PIN1 in normal human fibroblasts does not show any significant phenotype. 17 These results suggest that Pin1 could be crucial for tumor cells, and at least partially dispensable in normal cells. Different research groups are currently developing Pin1 small-molecule inhibitors, whose efficacy in anticancer therapy should be tested in vivo.…”

Section: Discussionmentioning

confidence: 90%

“…17 Collectively, these finding indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK, CDK inhibitor, and protein phosphatase activity.…”

mentioning

confidence: 93%

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Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 90%

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Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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“…Pin1 repré-sente une piste thérapeutique très intéressante pour certains cancers humains car (1) sa structure et ses modalités de fixation aux substrats sont bien décrites [4][5][6], (2) son inhibition diminue la progression tumorale dans plusieurs cancers [20,24], (3) des inhibiteurs de Pin1 ont été décrits dont la Juglone (5-hydroxy-1,4-naphtoquinone) [31] et le DTM (dipentaméthylène thiuram monosulfide) [32], et (4) les souris déficientes pour Pin1 sont viables [3], ce qui renforce l'hypothèse d'une possible utilisation des inhibiteurs de Pin1 comme traitements anticancéreux. Néanmoins, des études complémentaires sont essentielles pour développer des thérapies cellulaires ciblées avec une toxicité réduite pour l'organisme.…”

Section: Resultsunclassified

“…Pin1 est surexprimée dans de nombreux cancers humains comme le cancer du sein, de la prostate [19,20], du foie [21] ou encore de l'oesophage [22]. L'expression de Pin1 dans les cancers est associée aux derniers grades de la maladie et à un taux de survie faible [9,23].…”

Section: Pin1 Est Un Catalyseur Oncogéniqueunclassified

Pin1 : une peptidyl-prolylcis-transisomérase multifonctionnelle et une cible anticancéreuse prometteuse

Marsolier

Weitzman²

2014

Med Sci (Paris)

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> Les modifications post-traductionnelles sont essentielles pour contrôler finement les fonctions cellulaires des protéines. Un mécanisme peu connu, la peptidyl-prolyl cistrans isomérisation, joue également un rôle dans la régulation des protéines. Par exemple, la peptidyl-prolyl cis-trans isomérase Pin1 isomérise des motifs phosphorylés, induisant des changements structuraux de ses cibles et modulant ainsi leur stabilité, leur localisation, leur état de phosphorylation, leur activité et/ou leur interaction avec des partenaires. Pin1 est impliquée dans de nombreux processus cellulaires dont la prolifération et l'invasion cellulaires, ou encore l'induction et la maintenance de la pluripotence des cellules souches. De plus, Pin1 est surexprimée dans certains cancers humains. Ainsi, son inhibition constitue une piste thérapeutique prometteuse. < dans la structure de la protéine cible et régule ainsi ses fonctions. Les PPIases contrôlent donc de façon post-traductionnelle un grand nombre de protéines et sont impliquées dans de nombreux processus biologiques ou pathologiques humains (comme le cancer) [1]. Dans cette revue, nous nous intéresserons à Pin1 ainsi qu'à son rôle dans le développement des cellules tumorales. Structure et mécanismes d'action de Pin1Pin1 a été découverte lors d'un criblage double-hybride avec la protéine kinase mitotique NIMA (never in mitosis gene A) [2]. Chez la levure Saccharomyces cerevisiae, Pin1/Ess1 est la seule PPIase essentielle, ce qui démontre son importance biologique. Chez la levure, la délétion du gène est létale et induit un arrêt du cycle cellulaire [2]. Chez la souris, la délétion de Pin1 n'est pas létale, mais les souris mutantes présentent des phénotypes comparables à ceux des souris invalidées pour la cycline D1 [3]. Elles développent des anomalies de prolifération des tissus, comme une atrophie testiculaire, une dégéné-rescence de la rétine et un défaut de développement de l'épithélium mammaire lors de la gestation [3].

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BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells

et al. 2017

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Although widely deemed as a tumor suppressor gene, the role of B‐cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT‐qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT‐qPCR, or reporter assays. The 3H‐thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth. BTG2 expression was lower in human bladder cancer tissues than normal bladder tissues. Highly differentiated bladder cancer cells, RT4, expressed higher BTG2 than the less‐differentiated bladder cancer cells, HT1376 and T24. Overexpression of BTG2 in T24 cells inhibited cell growth in vitro and in vivo. Camptothecin and doxorubicin treatments in RT‐4 cells or transient overexpression of p53 into p53‐mutant HT1376 cells induced p53 and BTG2 expression. Further reporter assays with site‐mutation of p53 response element from GGGAAAGTCC to GGAGTCC within BTG2 promoter area showed that p53‐induced BTG2 gene expression was dependent on the p53 response element. Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression, while reverse effect was found in PTEN‐knockdown RT‐4 cells. PTEN activity inhibitor (VO‐OHpic) treatment decreased BTG2 expression in RT‐4 and PTEN‐overexpressed T24 cells. Our results suggested that BTG2 functioned as a bladder cancer tumor suppressor gene, and was induced by p53 and PTEN. Modulation of BTG2 expression seems a promising way to treat human bladder cancer.

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Stable Suppression of Tumorigenicity by Pin1-Targeted RNA Interference in Prostate Cancer

Cited by 103 publications

References 35 publications

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Pin1 : une peptidyl-prolylcis-transisomérase multifonctionnelle et une cible anticancéreuse prometteuse

BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells

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