Adrenocorticotropic hormone (ACTH)-secreting pituitary tumors mainly express somatostatin receptor 5 (SSTR5) since SSTR2 is downregulated by the elevated levels of glucocorticoids that characterize patients with Cushing’s disease (CD). SSTR5 is the molecular target of pasireotide, the only approved pituitary tumor-targeted drug for the treatment of CD. However, the molecular mechanisms that regulate SSTR5 are still poorly investigated. This review summarizes the experimental evidence supporting the role of the cytoskeleton actin-binding protein filamin A (FLNA) in the regulation of SSTR5 expression and signal transduction in corticotroph tumors. Moreover, the correlations between the presence of somatic USP8 mutations and the expression of SSTR5 will be reviewed. An involvement of glucocorticoid-mediated β-arrestins modulation in regulating SSTRs expression and function in ACTH-secreting tumors will also be discussed.
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- Author: Donatella Treppiedi x
Erika Peverelli, Donatella Treppiedi, and Giovanna Mantovani
Donatella Treppiedi, Rosa Catalano, Federica Mangili, Giovanna Mantovani, and Erika Peverelli
Cell cytoskeleton proteins are involved in tumor pathogenesis, progression and pharmacological resistance. Filamin A (FLNA) is a large actin-binding protein with both structural and scaffold functions implicated in a variety of cellular processes, including migration, cell adhesion, differentiation, proliferation and transcription. The role of FLNA in cancers has been studied in multiple types of tumors. FLNA plays a dual role in tumors, depending on its subcellular localization, post-translational modification (as phosphorylation at Ser2125) and interaction with binding partners. This review summarizes the experimental evidence showing the critical involvement of FLNA in the complex biology of endocrine tumors. Particularly, the role of FLNA in regulating expression and signaling of the main pharmacological targets in pituitary neuroendocrine tumors, pancreatic neuroendocrine tumors, pulmonary neuroendocrine tumors and adrenocortical carcinomas, with implications on responsiveness to currently used drugs in the treatment of these tumors, will be discussed.