title: Dopamine receptor type 2 (DRD2) inhibits migration and invasion of human tumorous pituitary cells through ROCK-mediated cofilin inactivation.
abstract: Non-functioning pituitary tumors (NFPTs) frequently present local invasiveness. Dopamine receptor 2 (DRD2) agonists are the only medical therapy that induces tumor shrinkage in some patients. Invasion requires cytoskeleton rearrangements that are tightly regulated by cofilin pathway, whose alterations correlate with invasion in different tumors. We investigated the effect of DR2D agonist on NFPT cells migration/invasion and the molecular mechanisms involved. We demonstrated that DRD2 agonist reduced migration (-44 ± 25%, p < 0.01) and invasion (-34 ± 6%, p < 0.001) and increased about 4-fold Ser3-phosphorylated inactive cofilin (P-cofilin) in NFPT cells. These effects were abolished by inhibiting ROCK, a kinase that phosphorylates cofilin. The overexpression of wild-type or phosphodeficient S3A-cofilin increased HP75 cells migration (+49 ± 6% and +57 ± 9% vs empty vector, respectively, p < 0.05), while phosphomimetic mutant had no effect. Interestingly, P-cofilin levels were lower in invasive vs non-invasive tumors by both western blot (mean P-cofilin/total cofilin ratio 0.77 and 1.93, respectively, p < 0.05) and immunohistochemistry (mean percentage of P-cofilin positive cells 17.6 and 45.7, respectively, p < 0.05). In conclusion, we showed that the invasiveness of pituitary tumors is promoted by the activation of cofilin, which can be regulated by DRD2 and might represent a novel biomarker for pituitary tumors' invasive behavior.
authors: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: erika.peverelli@guest.unimi.it.
authors: E
authors: E
authors: Peverelli
authors: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors: E
authors: E
authors: Giardino
authors: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors: D
authors: D
authors: Treppiedi
authors: Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors: M
authors: M
authors: Locatelli
authors: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM), Milan, Italy.
authors: V
authors: V
authors: Vaira
authors: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan Medical School, Milan, Italy.
authors: S
authors: S
authors: Ferrero
authors: Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors: S
authors: S
authors: Bosari
authors: Endocrine Unit, IRCCS Humanitas Clinical Institute, Rozzano, University of Milan, Milan, Italy.
authors: A G
authors: AG
authors: Lania
authors: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors: A
authors: A
authors: Spada
authors: Endocrine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors: G
authors: G
authors: Mantovani
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000970:Antineoplastic Agents; C581293:DRD2 protein, human; D018491:Dopamine Agonists; D047428:Protein Kinase Inhibitors; D017448:Receptors, Dopamine D2; D054460:rho-Associated Kinases
keywords: Cofilin; Dopamine receptor type 2; Invasion; Migration; Pituitary tumor