Spinophilin acts as a tumor suppressor by regulating Rb phosphorylation

Ferrer, Irene; Blanco‐Aparicio, Carmen; Peregrina, Sandra; Cañamero, Marta; Fominaya, Jesús; Cecilia, Yolanda; Lleonart, Matilde E.; Hernández‐Losa, Javier; Cajal, Santiago Ramón y; Carnero, Amancio

doi:10.4161/cc.10.16.16422

Cited by 31 publications

(32 citation statements)

References 67 publications

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“…As published in previous works (22), loss of Spn induces a molecular response very similar to that described in oncogen-induced senescence. This effect seems to be due to the inactivation of pRb which lead to E2F1 activation, p14ARF transcription, and consequently p53 activation.…”

Section: Discussionsupporting

confidence: 60%

“…Together with other reports on Spn (17)(18)(19)(20)22), our data suggest that the scaffolding protein Spn is important for the regulation of PP1a and pRb and that its absence may contribute to tumorigenesis in colorectal carcinomas. Mechanistically, the loss of Spn may induce a proliferative response by increasing pRb phosphorylation, which may influence the malignant phenotype and contribute to the failure of therapy in advanced stages of colorectal carcinoma.…”

Section: Discussionsupporting

confidence: 54%

“…Genetic and biochemical analyses have revealed a number of distinct modular domains in Spn that govern protein-protein interactions (17)(18)(19)(20)(21). Spn may contribute to tumorigenesis through PP1/pRB regulation (22). Accordingly, the loss of Spn maintains higher levels of phosphorylated retinoblastoma (Rb).…”

Section: Introductionmentioning

confidence: 99%

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Spinophilin Loss Correlates with Poor Patient Prognosis in Advanced Stages of Colon Carcinoma

Estévez-García

Lopez-Calderero

Molina-Pinelo

et al. 2013

Clinical Cancer Research

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Purpose: The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy.Experimental Design: By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy.Results: Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels.Conclusions: Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 54%

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Spinophilin Loss Correlates with Poor Patient Prognosis in Advanced Stages of Colon Carcinoma

Estévez-García

Lopez-Calderero

Molina-Pinelo

et al. 2013

Clinical Cancer Research

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“…Ferrer and colleagues demonstrated in mouse embryonic fibroblasts that the loss of spinophilin contributes to high levels of phosphorylated retinoblastoma protein (pRb) with the consequence of increased activation of the tumor suppressor p53 . In the absence of p53 or impaired function by mutation, the cells develop a pro-proliferative phenotype, given that the elevated pRb, which is normally neutralized by p53 , drives a pro-proliferative state [9]. However, in two recently published studies of hepatocellular carcinoma and CRC, loss of spinophilin was associated with p53- independent cellular proliferation [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Spinophilin expression determines cellular growth, cancer stemness and 5-flourouracil resistance in colorectal cancer

et al. 2014

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The putative tumor suppressor gene spinophilin has been involved in cancer progression in several types of cancer. In this study, we explored the prognostic value of spinophilin expression in 162 colon adenocarcinoma patients. In addition, we generated stably expressing spinophilin-directed shRNA CRC cell lines and studied the influence of spinophilin expression on cellular phenotypes and molecular interactions. We independently confirmed that low spinophilin expression levels are associated with poor prognosis in CRC patients (p = 0.038). A reduction of spinophilin levels in p53 wild-type HCT116 and p53-mutated Caco-2 cells led to increased cellular growth rates and anchorage-independent growth (p<0.05). At molecular level, reduced spinophilin levels increased the expression of the transcription factor E2F-1. In addition, we observed an increased formation of tumor spheres, increased number of CD133 positive cells and an increased resistance to 5-flourouracil (p<0.05). Finally, treatment with the de-methylating agent 5-aza-dC increased spinophilin expression in CRC cells (p<0.05), corroborated by a correlation of spinophilin expression and extent of methylated CpG sites in the gene promoter region (p<0.001). In conclusion, gain of aggressive biological properties of CRC cells including cellular growth, cancer stem cell features and 5-flourouracil resistance partly explains the role of spinophilin in CRC.

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“…En effet, les résultats de cette équipe indiquent que d'une part la surexpression ectopique de Spn dans des cellules MEF immortalisées réduit fortement la croissance cellulaire, et d'autre part qu'en l'absence de Spn (MEF Spn -/-), pRb est augmentée alors que parallèlement l'expression et l'activité de la PP1 diminuent [9]. Rb phosphorylée ne peut plus inhiber e2F1, provoquant dans un premier temps une prolifération 1 , suivie d'une augmentation de l'activité de ARF, induisant elle-même celle de p53.…”

Section: La Spinophiline Expression Tissulaire Et Partenairesunclassified

Levée de rideau sur la spinophiline, un suppresseur de tumeurs

Sarrouilhe

Ladevèze

2012

Med Sci (Paris)

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Spinophilin acts as a tumor suppressor by regulating Rb phosphorylation

Cited by 31 publications

References 67 publications

Spinophilin Loss Correlates with Poor Patient Prognosis in Advanced Stages of Colon Carcinoma

Spinophilin Loss Correlates with Poor Patient Prognosis in Advanced Stages of Colon Carcinoma

Spinophilin expression determines cellular growth, cancer stemness and 5-flourouracil resistance in colorectal cancer

Levée de rideau sur la spinophiline, un suppresseur de tumeurs

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