Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Vitali, Eleonora; Cambiaghi, Valeria; Zerbi, Alessandro; Carnaghi, Carlo; Colombo, Piergiuseppe; Peverelli, Erika; Spada, Anna; Mantovani, Giovanna; Lania, Andrea

doi:10.1530/erc-15-0358

Cited by 19 publications

(23 citation statements)

References 35 publications

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“…Moreover, SSTR2A is an attractive therapeutic target. An inhibitory effect of SST analogs on cell migration and invasion has been demonstrated in various tumors [ 3 , 24 , 31 , 34 ]. Moreover, therapy using radiolabeled SST analogs is commonly used as a therapeutic option for the treatment of metastatic or inoperable neuroendocrine tumors [ 5 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome

Appay¹,

Tabouret²,

Touat³

et al. 2018

acta neuropathol commun

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Diffuse gliomas are classified according to the 2016 WHO Classification of Tumors of the Central Nervous System, which now defines entities by both histology and molecular features. Somatostatin receptor subtype 2A (SSTR2A) expression has been reported in various solid tumors as associated with favorable outcomes. Its expression has been reported in gliomas with uncertain results regarding its prognostic value. The objective of this study was to assess the prognostic impact of SSTR2A protein expression in a large cohort of grade III and IV gliomas classified according to the updated 2016 WHO classification. We further validated our result with an independent cohort of low grade glioma using dataset generated by The Cancer Genome Atlas (TCGA) Research Network.We analyzed clinical and molecular data from 575 patients. SSTR2A protein expression was evaluated using immunohistochemistry on tissue microarrays. High expression of SSTR2A protein associated with the anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted subgroup (p < 0.001). Among these tumors, SSTR2A protein expression was significantly associated with a lower proliferative index, the absence of microvascular proliferation and the absence of necrosis (p < 0.001). Furthermore SSTR2A protein expression associated with better overall survival (p = 0.007) and progression-free survival (p = 0.01) in both univariate and multivariate analysis when adjusted by the age, the presence of necrosis and the mitotic index. Similar results were obtained regarding SSTR2 mRNA expression in the TCGA low grade glioma, subtype IDH-mutant and 1p/19q-codeleted, dataset.SSTR2A might represent an attractive biomarker and therapeutic target in anaplastic oligodendroglioma IDH-mutant and 1p/19q-codeleted specific subgroup. Understanding the implicated molecular pathways may represent a step forward to improve therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome

Appay¹,

Tabouret²,

Touat³

et al. 2018

acta neuropathol commun

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“…Similar results have been obtained in pancreatic neuroendocrine tumors (P-NET) that are currently treated with SSAs mainly targeted to SSTR2. FLNA silencing has a profound impact on SSTR2 signaling beside a marked reduced SSTR2 stability detected after long-term agonist incubation, both in primary cultured cells and in pancreatic neuroendocrine tumor cell line QGP-1 [85].…”

Section: Flnamentioning

confidence: 99%

Somatostatin Receptor Type 2 (SSTR2) Internalization and Intracellular Trafficking in Pituitary GH-Secreting Adenomas: Role of Scaffold Proteins and Implications for Pharmacological Resistance

et al. 2016

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Somatostatin receptor type 2 (SSTR2), together with SSTR5, represents the main target of medical treatment for growth hormone (GH)-secreting pituitary tumors, since it is expressed in most of these tumors and exerts both antiproliferative and cytostatic effects, and reduces hormone secretion, as well. However, clinical practice indicates a great variability in the frequency and entity of favorable responses of acromegalic patients to long-acting somatostatin analogues (SSAs), but the molecular mechanisms regulating this pharmacological resistance are not completely understood. So far, several potentially implied mechanisms have been suggested, including impaired expression of SSTRs, or postreceptor signal transduction alterations. More recently, new studies exploited the molecular factors involved in SSTRs intracellular trafficking regulation, this being a critical point for the modulation of the available active G-coupled receptors (GPCRs) amount at the cell surface. In this respect, the role of the scaffold proteins such as β-arrestins, and the cytoskeleton protein Filamin A (FLNA), have become of relevant importance for GH-secreting pituitary tumors. In fact, β-arrestins are linked to SSTR2 desensitization and internalization, and FLNA is able to regulate SSTR2 trafficking and stability at the plasma membrane. Therefore, the present review will summarize emerging evidence highlighting the role of β-arrestins and FLNA, as possible novel players in the modulation of agonist activated-SSTR2 receptor trafficking and response in GHsecreting pituitary tumors.

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“…The main pharmacological target of GH‐secreting pituitary tumors is the SS receptor type 2 (SST2), and long acting SS analogs reduce tumor growth and GH secretion in about 2/3 of patients. An inhibitory effect of SS on cell migration and invasion has been demonstrated in pancreatic neuroendocrine tumor cells, prostate carcinoma cells, neuroblastoma cells and endometrial cells while no data on pituitary tumors are available up to date. In addition, an effect of SS on cofilin phosphorylation has never been investigated, although data on neuroendocrine cells suggest a possible crosstalk between SS and cofilin pathway …”

Section: Introductionmentioning

confidence: 99%

“…In addition, an effect of SS on cofilin phosphorylation has never been investigated, although data on neuroendocrine cells suggest a possible crosstalk between SS and cofilin pathway. 13,17 A role for cell cytoskeleton in pituitary tumors responsiveness to DA and SS analogs has recently been demonstrated. [18][19][20] SST2 directly interacts with filamin A (FLNA), 19,21 a large actin binding protein able to homodimerize, composed of an N-terminal actin-binding domain and 24 Ig-like repeats of about 96 aminoacids.…”

Section: Introductionmentioning

confidence: 99%

A novel pathway activated by somatostatin receptor type 2 (SST2): Inhibition of pituitary tumor cell migration and invasion through cytoskeleton protein recruitment

Peverelli

Giardino

Treppiedi

et al. 2017

Intl Journal of Cancer

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The pharmacological therapy of GH-secreting pituitary tumors is based on somatostatin (SS) analogs that reduce GH secretion and cell proliferation by binding mainly SS receptors type 2 (SST2). Antimigratory effects of SS have been demonstrated in different cell models, but no data on pituitary tumors are available. Aims of our study were to evaluate SST2 effects on migration and invasion of human and rat tumoral somatotrophs, and to elucidate the molecular mechanism involved focusing on the role of cofilin and filamin A (FLNA). Our data revealed that SST2 agonist BIM23120 significantly reduced GH3 cells migration (-22% ± 3.6%, p < 0.001) and invasion on collagen IV (-31.3% ± 12.2%, p < 0.01), both these effects being reproduced by octreotide and pasireotide. Similar results were obtained in primary cultured cells from human GH-secreting tumors. These inhibitory actions were accompanied by a marked increase in RhoA/ROCK-dependent cofilin phosphorylation (about 2.7-fold in GH3 and 2.1-fold in human primary cells). Accordingly, the anti-invasive effect of the SS analog was mimicked by the overexpression in GH3 cells of the S3D phosphomimetic cofilin mutant, and abolished by both phosphodeficient S3A cofilin and a specific ROCK inhibitor that prevented cofilin phosphorylation. Moreover, FLNA silencing and FLNA dominant-negative mutants FLNA19-20 and FLNA21-24 transfection demonstrated that FLNA plays a scaffold function for SST2-mediated cofilin phosphorylation. Accordingly, cofilin recruitment to agonist-activated SST2 was completely lost in FLNA silenced cells. In conclusion, we demonstrated that SST2 inhibits rat and human tumoral somatotrophs migration and invasion through a molecular mechanism that involves FLNA-dependent cofilin recruitment and phosphorylation.

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Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Cited by 19 publications

References 35 publications

Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome

Somatostatin receptor 2A protein expression characterizes anaplastic oligodendrogliomas with favorable outcome

Somatostatin Receptor Type 2 (SSTR2) Internalization and Intracellular Trafficking in Pituitary GH-Secreting Adenomas: Role of Scaffold Proteins and Implications for Pharmacological Resistance

A novel pathway activated by somatostatin receptor type 2 (SST2): Inhibition of pituitary tumor cell migration and invasion through cytoskeleton protein recruitment

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